1-155235252-A-G

Variant names:

• chr1-155235252-A-G
• rs421016
• NM_000157.4:c.1448T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM5 PP2 PP3 PP5_Very_Strong BP4

The NM_000157.4(GBA1):​c.1448T>C​(p.Leu483Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic,risk factor (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L483R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000084 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Pathogenic; risk factor criteria provided, multiple submitters, no conflicts P:42 O:5
• Conservation: PhyloP100: 7.95
• Publications: 1134 publications found

Genes affected

GBA1 (HGNC:4177): (glucosylceramidase beta 1) This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]

GBA1 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Gaucher disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• Gaucher disease perinatal lethal

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• late-onset Parkinson disease

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Gaucher disease type I

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Gaucher disease type II

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Gaucher disease type III

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235252-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 93449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.1739 (below the threshold of 3.09). Trascript score misZ: 2.2879 (below the threshold of 3.09). GenCC associations: The gene is linked to late-onset Parkinson disease, Gaucher disease perinatal lethal, Gaucher disease, Gaucher disease type I, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease type II, Parkinson disease, Gaucher disease type III.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 1-155235252-A-G is Pathogenic according to our data. Variant chr1-155235252-A-G is described in ClinVar as Pathogenic|risk_factor. ClinVar VariationId is 4288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19879305). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4	c.1448T>C	p.Leu483Pro	missense_variant	Exon 10 of 11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.1448T>C	p.Leu483Pro	missense_variant	Exon 10 of 11	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151964 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00130 AC: 324 AN: 250058 AF XY: 0.00124

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00252

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00147

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000842 AC: 123 AN: 1460902 Hom.: 0 Cov.: 32 AF XY: 0.0000798 AC XY: 58 AN XY: 726764

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000120 AC: 4 AN: 33438

American (AMR) AF: 0.000112 AC: 5 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26118

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39658

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86214

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53362

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.0000675 AC: 75 AN: 1111332

Other (OTH) AF: 0.000149 AC: 9 AN: 60338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000237 AC: 36 AN: 152080 Hom.: 0 Cov.: 25 AF XY: 0.000256 AC XY: 19 AN XY: 74322

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000434 AC: 18 AN: 41492

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4808

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00253 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00315 AC: 383

ClinVar

Significance: Pathogenic; risk factor

Submissions summary: Pathogenic:42 Other:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GBA1: PM3:Very Strong, PM5, PM2:Supporting, PS3:Supporting -

Feb 23, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PP3, PM1, PM2, PM5 -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GBA c.1448T>C; p.Leu483Pro variant (rs421016, ClinVar Variation ID: 4288, also known as Leu444Pro for legacy nomenclature), is reported in the literature in the homozygous or compound heterozygous state in numerous individuals affected with Gaucher disease (Grace 1994, Ivanova 2018, Montfort 2004, Saranjam 2013). This variant is found in the general population with an overall allele frequency of 0.12% (345/281386 alleles) in the Genome Aggregation Database (v2.1.1). Despite its occurrence in the population, the p.Leu483Pro variant has also been observed to occur de novo in several affected individuals (Saranjam 2013). Computational analyses predict that this variant is deleterious (REVEL: 0.858). Consistent with predictions, functional studies in both patient-derived cells and cultured cell lines demonstrate enzymatic activity of the variant protein at <10% of normal (Grace 1994, Ivanova 2018, Montfort 2004). Based on available information, this variant is considered to be pathogenic. References: Grace ME et al Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. J Biol Chem. 1994 Jan 21;269(3):2283-91. PMID: 8294487. Ivanova MM et al. Individualized screening for chaperone activity in Gaucher disease using multiple patient derived primary cell lines. Am J Transl Res. 2018 Nov 15;10(11):3750-3761. PMID: 30662625. Montfort M et al. Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms. Hum Mutat. 2004 Jun;23(6):567-75. PMID: 15146461. Saranjam H et al. A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders. Eur J Hum Genet. 2013 Jan;21(1):115-7. PMID: 22713811. -

May 02, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 483 of the GBA protein (p.Leu483Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with dementia with Lewy bodies, Gaucher disease, and/or Parkinson's disease (PMID: 8929950, 18987351, 20816920, 22713811, 23588557, 23676350, 25249066, 25535748, 26096741, 27094865). This variant is also known as p.Leu444Pro. ClinVar contains an entry for this variant (Variation ID: 4288). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBA protein function. Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 15146461, 24020503). This variant disrupts the p.Leu483 amino acid residue in GBA. Other variant(s) that disrupt this residue have been observed in individuals with GBA-related conditions (PMID: 7981693), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Jan 13, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect indicating that this variant is poorly activated by phosphatidylserine, is unstable and has residual enzyme activity of 5-10% of wild type (Grace et al., 1994; Malini et al., 2014); Identified in the heterozygous state in patients with Lewy body dementia and with Parkinson disease with dementia; however, L483P was also identified in the heterozygous state in control individuals used in these studies (Mata et al., 2008; Nalls et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Previously reported as L444P due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 21472771, 21106416, 8294487, 31561936, 23286447, 23227814, 23642305, 21700325, 21700212, 21856586, 22220748, 23635853, 24022302, 22713811, 23783781, 22975760, 20643691, 15146461, 22623374, 23588557, 16293621, 22006919, 25333069, 21742527, 21745757, 22227073, 20131388, 23676350, 24126159, 20004703, 20816920, 18347322, 18987351, 24020503, 25535748, 22160715, 23277556, 22192918, 25249066, 21228398, 8607360, 2880291, 27014572, 18332251, 27094865, 26096741, 27717005, 27153395, 19846850, 27865684, 16967369, 29934114, 11336129, 29625627, 24195576, 29602947, 29140481, 29396846, 28894968, 28003644, 8929950, 10714667, 24095219, 8160756, 30146349, 30548430, 27896091, 29842932, 30537300, 29029963, 29487000, 31193028, 30941926, 30606667, 31216804, 30456712, 31130284, 29471591, 33083013, 32618053, 32883051, 33763395, 33176831, 32658388) -

Gaucher disease type I Pathogenic:9

Jan 03, 2019

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The variant NM_000157.4: c.1448T>C(p.L483P) in exon-10 of GBA gene has been seen in heterozygous status. It is the most common mutation in Indian patients affected with Gaucher's Disease. -

Oct 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 26, 2021

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Traditional Chinese Medicine, Fujian Provincial Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

A patient with combined splenomegaly and thrombocytopenia was genetically tested for mutant GBA (NM_001005741): c.1448T>C (p.Leu483Pro), which is a missense mutation in exon 11, for which damage to protein function is predicted by:SIFT: Deleterious; Polyphen2: Possibly damaging; MutationTaster: disease causing automatic. According to the ACMG guidelines, this mutation site meets: PS3: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product; PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation; PM3: For recessive disorders, detected in trans with a pathogenic variant; and PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). This mutation has been reported to cause "Gaucher disease"( PMID: 2880291) and is therefore considered "Pathogenic". -

Oct 30, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_001005741.2(GBA):c.1448T>C(L483P, aka L444P) is classified as pathogenic in the context of Gaucher disease. The L483P variant can be associated with either Type 1, 2 or 3 Gaucher disease. Sources cited for classification include the following: PMID 2880291, 15146461, 21106416, 27123474 and 9375849. Classification of NM_001005741.2(GBA):c.1448T>C(L483P, aka L444P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

May 18, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1448T>C (p.Leu483Pro) variant has been previously reported in homozygous or compound heterozygous state in individuals affected with Gaucher Disease (Grabowski et al, 2015). Experimental studies have shown that this missense change affects GBA function (Migdalska-Richards A, et. al., 2017). This variant is reported with the allele frequency (0.1%) in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar with varying interpretations as Likely Pathogenic/ Pathogenic (multiple submissions). The amino acid Leucine at position 483 is changed to a Proline changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

-

Dr.Nikuei Genetic Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gaucher disease Pathogenic:7 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Leu483Pro variant in GBA has been reported in at least 89 individuals with Gaucher disease (PMID: 17427031, 23719189, 30662625) and has been identified in 0.245% (25/10202) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs421016). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role and is consistent with the increased prevalence of Gaucher disease in the Ashkenazi Jewish population. This variant has also been reported in ClinVar (VariationID: 4288) as pathogenic by EGL Genetic Diagnostics, Counsyl, GeneDx, Integrated Genetics, Mayo Clinic Genetic Testing Laboratories, Foundation for Research in Genetics and Endocrinology, and OMIM and as likely pathogenic by Praxis fuer Humangenetik Tuebingen. Animal models in mice have shown that this variant causes Gaucher disease (PMID: 28686011). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Leu483Arg, has been reported in association with disease in the literature and ClinVar, raising the possibility that a change at this position may not be tolerated (VariationID: 93449; PMID: 27825739). The phenotype of 11 individuals homozygous or compound heterozygous for this variant is highly specific for Gaucher Disease based on beta-glucosidase residual activity <10% of normal, consistent with disease (PMID: 30662625, 23719189). The presence of this variant in 16 affected homozygotes and in combination with reported pathogenic variants (VariationID: 4290, 4293, 4327, 21070, 193611, 4314; PMID: 17427031, 23719189, 30662625) in 67 individuals with Gaucher disease increases the likelihood that the p.Leu483Pro variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the presence of the variant in affected individuals and in combination with other pathogenic variants, functional studies, and the phenotype of individuals with this variant being highly specific for Gaucher disease. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PP3, PP4 (Richards 2015). -

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CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GBA c.1448T>C (p.Leu483Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 250058 control chromosomes (gnomAD). c.1448T>C has been reported in the literature in multiple individuals affected with Gaucher Disease (Miocic_ 2005, Malini_2013, Siebert_2013, Tammachote_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies report the variant effect results in decreasing GBA enzyme activity in transfected cells (Alfonso__2004, Malini_2013). 12 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=11) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gaucher disease. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported (PMID: 31010158). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2; 345 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Glyco_hydro_30C domain (NCBI, PDB, DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in both homozygotes and compound heterozygotes with Gaucher disease (Clinvar; PMID: 24022302, 27014572, 26096741). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated 13% residual enzymatic activity (PMID: 24022302). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000157.3(GBA):c.1342G>C; p.(Asp448His)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 8294487; 15146461; 30285649; 28969384) - PS3_moderate.The c.1448T>C;p.(Leu483Pro) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 4288; PMID: 28727984; PMID: 28947706; PMID: 28894968; PMID: 28546865; PMID: 20301446; PMID: 26096741; PMID: 8929950; PMID: 22713811; PMID: 25249066; PMID: 20816920; PMID: 27094865; PMID: 25535748; PMID: 18987351; PMID: 23588557) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Glyco_hydro_30C) - PM1. The variant is present at low allele frequencies population databases (rs421016 – gnomAD 0.01226%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Leu483Pro) was detected in trans with a pathogenic variant (PMID: 24522292) - PM3. Pathogenic missense variant in this residue have been reported (Clinvar ID: 93449) - PM5. Missense variant in GBA that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. In summary, the currently available evidence indicates that the variant is pathogenic. -

Aug 31, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Gaucher disease type II Pathogenic:4

Oct 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2018

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The observed variant c.1448T>C (p.Leu483Pro) has a minor allele frequency of 0.0034 in 1000 Genomes and 0.003099 in ExAC databases. The in silico prediction of the given variant is disease causing by MutationTaster2, damaging by SIFT and possibly damaging by PolyPhen2. This variant was detected as a compound heterozygous along with another variant c.1448T>G (p.Leu483Arg). The variant c.1448T>G (p.Leu483Arg) was neither found in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is disease causing by MutationTaster2, damaging by SIFT and probably damaging by PolyPhen2. -

Jul 07, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Gaucher disease type III Pathogenic:3

Oct 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Parkinson disease, late-onset Pathogenic:2 Other:1

Oct 01, 2013

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 29, 2020

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2024

Genetics Department, Catlab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1448T>C variant in the GBA gene has been previously associated to Parkinson disease in a case-control study (odds ratio, OR=13.76, 95% Confidence interval, CI: 1.84-102.92, p=0.001, PMID: 20004703) (PS4) and functional in vivo abd in vitro studies have shown that the variant impairs the activity (PMID: 28969384, 24022302, 8294487) (PS3_strong). Additionally, the variant has an extremely low presence in gnomAD 4.1 (AF= 9.8575e-05) (PM2). The c.1448T>G variant producing an amino acid change in the same position has been previously described as (PM5). With all the available evidence, the variant is classified as pathogenic. -

Gaucher disease perinatal lethal Pathogenic:2 Other:1

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GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 12-06-2012 by Baylor College of Medicine. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Nov 02, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM5,PP3,PP5,PS1,PS3. -

Jan 21, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PP3, PS3, PP5 -

Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I Pathogenic:1

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Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GBA1-related disorder Pathogenic:1

Aug 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GBA1 c.1448T>C variant is predicted to result in the amino acid substitution p.Leu483Pro. This variant is the second most prevalent variant in Gaucher disease (Alfonso et al. 2007. PubMed ID: 17427031) and the most common GBA mutation leading to the Type 3 (GD3) of Gaucher disease (Ivanova et al. 2018. PubMed ID: 30662625). This variant was observed in homozygous and compound heterozygous state in multiple individuals with Gaucher disease (Tsuji et al. 1987. PubMed ID: 2880291; Grabowski et al, 2015 PubMed ID: 26096741; Alfonso et al. 2007. PubMed ID: 17427031; Tammachote et al. 2013. PubMed ID: 23719189; Ivanova et al. 2018. PubMed ID: 30662625) and in heterozygous state in individuals with Parkinson disease or dementia with Lewy bodies (Nichols 2009 PubMed ID: 18987351; Santos 2010 PubMed ID: PMID: 20816920; Nalls et al. 2013. PubMed ID: 23588557). Beta-glucosidase residual activity in individuals homozygous and compound heterozygous for this variant is reported below <10% of normal, consistent with Gaucher disease (Ivanova et al. 2018. PubMed ID: 30662625; Tammachote et al. 2013. PubMed ID: 23719189). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic for Gaucher disease, but a risk factor for Parkinson disease. XXXXXXXXXXXXXXXXXXXXX This variant can be also a part of pathogenic recombinant alleles RecNciI c.[1448T>C;1483G>C;1497G>C] or RecTL c.[1342G>C;1448T>C;1483G>C;1497G>C] . If other variants are also present in the patient, use RecNciI or RecTL variant interpretation text in Variant notes XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX -

Lewy body dementia Pathogenic:1

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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not specified Pathogenic:1

Feb 01, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1448T>C (p.L483P) alteration is located in exon 11 (coding exon 10) of the GBA gene. This alteration results from a T to C substitution at nucleotide position 1448, causing the leucine (L) at amino acid position 483 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.12% (345/281386) total alleles studied. The highest observed frequency was 0.25% (25/10202) of Ashkenazi Jewish alleles. The c.1448T>C (p.L483P) alteration, legacy name p.L444P, is a common pathogenic variant in GBA (Tsuji, 1988; Asselta, 2014; Malini, 2014). Homozygosity is typically associated with Gaucher disease type 3 (subacute, juvenile onset), while heterozygosity for p.L483P with a different GBA pathogenic variant may be associated with Gaucher disease type 2 (acute, infantile onset). The p.L483P mutation appears to be common in affected individuals of Swedish, Japanese, and Ashkenazi Jewish descent (Stone, 2000; Koprivica, 2000; Hruska, 2008). The p.L483 amino acid is conserved in available vertebrate species. Functional analysis of the L483P mutant protein expressed in HEK293 cells revealed that residual GBA activity was 13% as compared to wild-type (Malini, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset Pathogenic:1

Feb 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Pathogenic:1

Oct 10, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.123%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15146461, 28969384). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.86 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000004288) and different missense changes at the same codon (p.Leu483, p.Leu483Arg / ClinVar ID: VCV000093449) has been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Movement disorder;C0234379:Resting tremor;C0242422:Parkinsonian disorder;C0749379:Thoracolumbar scoliosis;C0813217:Hypomimic face Other:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: risk factor

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Dementia, Lewy body, susceptibility to Other:1

Oct 01, 2013

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.60	.;T;T;T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.94	P;P;.;.
Vest4		0.96
MVP		0.94
MPC		2.3
ClinPred		0.10	T
GERP RS		3.2
Varity_R		0.97
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs421016; hg19: chr1-155205043;