rs1064651

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000157.4(GBA1):ā€‹c.1342G>Cā€‹(p.Asp448His) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,613,424 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00020 ( 0 hom., cov: 30)
Exomes š‘“: 0.00010 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

7
5
7

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28O:1

Conservation

PhyloP100: 5.37
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-155235727-C-G is Pathogenic according to our data. Variant chr1-155235727-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155235727-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GBA1NM_000157.4 linkuse as main transcriptc.1342G>C p.Asp448His missense_variant 9/11 ENST00000368373.8 NP_000148.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GBA1ENST00000368373.8 linkuse as main transcriptc.1342G>C p.Asp448His missense_variant 9/111 NM_000157.4 ENSP00000357357 P1P04062-1

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152014
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.000218
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000128
AC:
32
AN:
250360
Hom.:
0
AF XY:
0.000126
AC XY:
17
AN XY:
135308
show subpopulations
Gnomad AFR exome
AF:
0.000124
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000656
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000185
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000103
AC:
151
AN:
1461294
Hom.:
0
Cov.:
32
AF XY:
0.0000922
AC XY:
67
AN XY:
726862
show subpopulations
Gnomad4 AFR exome
AF:
0.000299
Gnomad4 AMR exome
AF:
0.000247
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.0000697
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000998
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152130
Hom.:
0
Cov.:
30
AF XY:
0.000175
AC XY:
13
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000321
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000906
AC:
11

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:28Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Gaucher disease type I Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingGenetic Diagnostics Department, Viafet Genomics LaboratoryApr 05, 2016As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant has been identified in a homozygous and compound heterozygous state in patients affected with Gaucher disease type I, II or IIIC (PMIDs: 33176831, 31130326, 31026225, 25946768, 19816973 and 11992489). -
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 20, 2019NM_001005741.2(GBA):c.1342G>C(D448H) is classified as likely pathogenic in the context of Gaucher disease. Sources cited for classification include the following: PMID 15146461, 2269438, 11992489, 16293621, 19816973, 11359469 and 8544197. Classification of NM_001005741.2(GBA):c.1342G>C(D448H) is based on the following criteria: This variant 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 submitterclinical testingFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsAug 19, 2023A Homozygous variation in exon 9 of the GAA gene that results in the amino acid substitution of Histidine for Aspartic acid at codon 448 was detected. The observed variant has not been reported in the 1000 genomes and gnomAD databases. The in-silico prediction of the variant is disease causing by MutationTaster2, DANN and FATHMM. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Medical Genetics, National & Kapodistrian University of AthensSep 28, 2022PS3, PM1, PM2, PP2, PP5 -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 06, 2021Based 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 (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. The different types of Gaucher disease are considered to fall within a spectrum, rather than distinct conditions, and are determined by age of disease onset and the presence and severity of neurologic function. Specific counseling about individual case prognosis is hindered by a significant overlap in the clinical features of individuals with various genotypes (OMIM, GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported, with monozygotic twins displaying a disordant phenotype (PMID: 31010158, GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (38 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glycosyl hydrolase family 30 TIM-barrel domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in at least ten individuals with Gaucher disease (ClinVar, PMID: 31130326). Individuals homozygous for this variant also tend to develop cardiovascular disease (GeneReviews). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000157.3(GBA):c.887G>A; p.(Arg296Gln)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 23, 2024This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 448 of the GBA protein (p.Asp448His). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individuals with GBA-related conditions (PMID: 8544197, 11992489, 15146461, 19816973, 25946768). ClinVar contains an entry for this variant (Variation ID: 4293). 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, 16293621, 21257328). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2023GBA1: PM3:Very Strong, PS3:Moderate, PM2:Supporting, PM5:Supporting, PP3 -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 24, 2023- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 17, 2021Functional analysis of D448H found that it is associated with significantly reduced beta-glucocerebrosidase enzyme activity (Grace et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Previously reported as D409H due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 19816973, 9040001, 19286695, 9061570, 10447266, 10796875, 11992489, 23588557, 16293621, 21742527, 2269438, 21700325, 15146461, 29934114, 30637984, 31709146, 31996268, 8294487, 22975760, 21745757, 24126159, 20816920, 7627184, 10360404, 21472771, 21257328, 8544197, 27312774, 26096741, 27717005, 25946768, 26887759, 29656334, 28894968, 10714667, 14578207, 8160756, 30528841, 31026225, 28393750, 31130326, 30410382, 28040394, 31216804, 31589614, 32677286, 9556036, 32618053, 33763395, 33176831, 32658388, 32714263) -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 15, 2022- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 20, 2016- -
Gaucher disease Pathogenic:3Other:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 23, 2016Variant summary: The GBA c.1342G>C (p.Asp448His) variant, alternatively also known as D409H, involves the alteration of a conserved nucleotide, is located in Glycoside hydrolase superfamily domain (InterPro) and is predicted to be damaging by 2/4 in silico tools. This variant was found in 11/100268 control chromosomes at a frequency of 0.0001097, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant is widely reported as a pathogenic variant with consistent genotype-phenotype and functional study data. The allele frequency of this variant from a cohort of all GD patients (n=436) registered in Portugal and Spain was 28/872 (3.3%). The variant typically causes severe form of disease (i.e. GD type 3) when present in homozygous state. Another missense variant at this residue D448V is also a known pathogenic variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Mar 17, 2017- -
Pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJan 22, 2020The p.Asp448His variant in GBA has been reported in at least 33 individuals with Gaucher disease (PMID: 17427031, 8213821, 18586596, 11933202, 19816973) and has been identified in 0.020% (7/34432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1064651). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 4293) as likely pathogenic by Counsyl and as pathogenic by EGL Genetic Diagnostics, GeneDx, Integrated Genetics, Fulgent Genetics, Mayo Clinic Genetic Testing Laboratories, and OMIM. Animal models in mice have shown that this variant causes Gaucher disease based on visceral disease and decreased beta-glucosidase levels (PMID: 16061944). 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.Asp448Val, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 2349952, 17509920, 28223512, 2508065; Variation ID: 4294). Additionally, the homozygous occurrence of this variant in at least 23 individuals with Gaucher disease and the presence of this variant in combination with reported pathogenic variants in at least 9 individuals with Gaucher disease (VariationID: 4327, 4288, 03445; PMID: 17427031, 8213821, 18586596, 11933202, 19816973) increases the likelihood that the p.Asp448His 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 multiple occurrences of the variant in affected individuals who are homozygous or compound heterozygous with another pathogenic variant, mouse models showing the variant to be damaging, and computational tools. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PM2_supporting, PM5_supporting, PP3 (Richards 2015). -
not provided, no classification providedliterature onlyGeneReviews-- -
Gaucher disease perinatal lethal Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLifecell International Pvt. Ltd-A Heterozygous Missense variant c.1342G>C in Exon 9 of the GBA1 gene that results in the amino acid substitution p.Asp448His was identified. The observed variant has a minor allele frequency of 0.00013 in gnomAD exomes and is novel in genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic [Variation ID: 4293]. The observed variant has been previously reported in patients affected with Gaucher disease (Kurolap, Alina et al., 2019). Furthermore, experimental studies have shown that this missense change affects GBA function (Xu, Y H et al., 2011). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaApr 01, 2020This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM2,PM3,PP3,PS1_SUP. -
Parkinson disease, late-onset Pathogenic:2
Pathogenic, criteria provided, single submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 17, 2024- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 03, 2021- -
Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGenetic Diagnostics Department, Viafet Genomics LaboratoryApr 05, 2016As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant has been identified in a homozygous and compound heterozygous state in patients affected with Gaucher disease type I, II or IIIC (PMIDs: 33176831, 31130326, 31026225, 25946768, 19816973 and 11992489). -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -
Gaucher disease type II Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGenetic Diagnostics Department, Viafet Genomics LaboratoryApr 05, 2016As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant has been identified in a homozygous and compound heterozygous state in patients affected with Gaucher disease type I, II or IIIC (PMIDs: 33176831, 31130326, 31026225, 25946768, 19816973 and 11992489). -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 13, 2015The p.D448H pathogenic mutation (also known as c.1342G>C and p.D409H), located in coding exon 9 of the GBA gene, results from a G to C substitution at nucleotide position 1342. The aspartic acid at codon 448 is replaced by histidine, an amino acid with a few similar properties. This mutation is one of six common mutations that together account for 60-70% of Gaucher disease causing alleles in Caucasian populations and is the third most frequent mutation in Spanish patients, accounting for more than 5% of all mutated Spanish alleles (Chabas et al. J. Med. Genet. 1995;32(9):740-2; Matto&scaron;ov&aacute; S, et al. Isr. Med. Assoc. J. 2015;17(3):166-70). Individuals who are homozygous for this mutation generally have cardiac calcifications, ocular manifestations, and neurological disease, but variable presentation of organomegaly (Chabas et al. J. Med. Genet. 1995;32(9):740-2; Abrahamov et al. Lancet 1995;346(8981):1000-3). Both in vivo and in vitro studies have shown that this mutation demonstrates reduced enzyme activity (4- 9% of wild type) (Montfort et al. Hum. Mutat. 2004;23(6):567-75). Compound heterozygous individuals have also been reported to have Parkinson disease symptoms and cardiac manifestations along with classic Gaucher disease symptoms (Orvinsky et al. Hum. Mutat. 2002;19(4):458-9; Li Y, Neurobiol. Aging 2014 Apr; 35(4):935.e3-8). Based on the supporting evidence, p.D448H is interpreted as a disease-causing mutation. -
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 submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 16, 2021- -
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 submitterclinical testingBaylor Genetics-- -
Gaucher disease type III Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.40
CADD
Uncertain
24
DANN
Benign
0.97
DEOGEN2
Pathogenic
0.97
D;D;.;.
Eigen
Benign
0.048
Eigen_PC
Benign
0.11
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.79
.;T;T;T
M_CAP
Pathogenic
0.44
D
MetaRNN
Uncertain
0.73
D;D;D;D
MetaSVM
Pathogenic
1.2
D
MutationAssessor
Uncertain
2.8
M;M;.;.
MutationTaster
Benign
1.0
A;A;A;A;A
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.6
D;D;D;D
REVEL
Pathogenic
0.74
Sift
Benign
0.069
T;T;T;T
Sift4G
Benign
0.091
T;T;T;T
Polyphen
0.20
B;B;.;.
Vest4
0.65
MVP
0.97
MPC
0.93
ClinPred
0.16
T
GERP RS
3.5
Varity_R
0.76
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.21
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.21
Position offset: 46

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1064651; hg19: chr1-155205518; COSMIC: COSV59168989; COSMIC: COSV59168989; API