1-155235252-A-G

Position:

• chr1-155235252-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM5 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:40 O:5
• Conservation: PhyloP100: 7.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235252-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, MutationAssessor, phyloP100way_vertebrate, PROVEAN, 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 id is 4288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155235252-A-G is described in Lovd as [Pathogenic]. Variant chr1-155235252-A-G is described in Lovd as [Likely_pathogenic]. Variant chr1-155235252-A-G is described in Lovd as [Pathogenic].
• 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/exons	MANE	UniProt
GBA1	NM_000157.4	c.1448T>C	p.Leu483Pro	missense_variant	10/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1448T>C	p.Leu483Pro	missense_variant	10/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 36 AN: 151964 Hom.: 0 Cov.: 25 FAILED QC

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

GnomAD3 exomes AF: 0.00130 AC: 324 AN: 250058 Hom.: 0 AF XY: 0.00124 AC XY: 168 AN XY: 135150

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 SAS exome AF: 0.000688

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

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.0000675

Gnomad4 OTH exome AF: 0.000149

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

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

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:40 Other:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 13, 2020	PS3, PP3, PM1, PM2, PM5 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 06, 2022	The GBA c.1448T>C; p.Leu483Pro variant (rs421016), also known as Leu444Pro, 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. Despite its occurrence in the population, the p.Leu483Pro variant has also been observed to occur de novo in several affected individuals (Saranjam 2013). The leucine at codon 483 is highly conserved, and 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, the p.Leu483Pro 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. 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. 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. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	GBA1: PM3:Very Strong, PM5, PS3:Moderate, PM2:Supporting -

Gaucher disease type I Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jan 03, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 30, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Nov 26, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2013	- -
Pathogenic, no assertion criteria provided	literature only	Department of Traditional Chinese Medicine, Fujian Provincial Hospital	-	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". -
Pathogenic, no assertion criteria provided	clinical testing	Dr.Nikuei Genetic Center	-	- -

Gaucher disease Pathogenic:6 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2021	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. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	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. -

Gaucher disease type II Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jun 29, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 07, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

Gaucher disease type III Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004288, PS1_S).Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 28969384, 15146461, PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093449, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.858, 3CNET: 0.995, PP3_P). A missense variant is a common mechanism associated with Parkinson disease (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
risk factor, no assertion criteria provided	literature only	OMIM	Oct 01, 2013	- -

Gaucher disease perinatal lethal Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 02, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM5,PP3,PP5,PS1,PS3. -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	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/. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 21, 2020	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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

GBA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2024

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

Pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 17, 2024

- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 08, 2022

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

risk factor, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

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Dementia, Lewy body, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Oct 01, 2013

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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;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs421016; hg19: chr1-155205043;