ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1246G>A (p.Gly416Ser) (rs121908311)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723428 SCV000700355 pathogenic not provided 2017-04-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000055772 SCV000917432 pathogenic Gaucher disease 2018-08-09 criteria provided, single submitter clinical testing Variant summary: GBA c.1246G>A (p.Gly416Ser) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain 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 1.4e-05 in 277220 control chromosomes (gnomAD). The variant, c.1246G>A, has been reported in the literature in multiple individuals affected with Gaucher Disease in the homozygous and compound heterozygous state. These data indicate that the variant is very likely to be associated with disease. A functional study showed the variant to have <10% activity compared to wild-type (Amaral_2000). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000004571 SCV000930234 pathogenic Gaucher disease type I 2019-04-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004116 SCV001162847 pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease type 3C criteria provided, single submitter clinical testing
OMIM RCV000004571 SCV000024745 pathogenic Gaucher disease type I 2003-03-01 no assertion criteria provided literature only
OMIM RCV000004572 SCV000024746 pathogenic Gaucher disease type III 2003-03-01 no assertion criteria provided literature only
GeneReviews RCV000055772 SCV000086731 pathologic Gaucher disease 2013-09-19 no assertion criteria provided curation Converted during submission to Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000055772 SCV001423053 pathogenic Gaucher disease 2020-01-22 no assertion criteria provided curation The p.Gly416Ser variant in GBA has been reported in at least 25 individuals with Gaucher disease (PMID: 25946768, 16981045, 23430543, 25732996, 17395504) and has been identified in 0.003% (4/129180) of European (non-Finnish) chromosomes and 0.002822% (1/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908311). 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: 4327) as pathogenic by EGL Gene Diagnostics, OMIM, and Integrated Genetics. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, the homozygous occurrence of this variant in 9 affected individuals and the presence of this variant in combination with a reported pathogenic variant in 11 individuals with Gaucher disease increases the likelihood that the p.Gly416Ser variant is pathogenic (VariationID: 4290, 4288; PMID: 25946768, 16981045, 23430543, 25732996, 17395504). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Gaucher disease based on enzyme activity of less than 1.7 nmol/h/mg protein, consistent with disease (PMID: 25946768, 16981045, 25732996). 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 homozygotes and in combination with other pathogenic variants in affected individuals, the phenotype of affected individuals with the variant that is specific to the disease, and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP4 (Richards 2015).
Birmingham Platelet Group; University of Birmingham RCV001270486 SCV001450785 pathogenic Abnormal bleeding; Thrombocytopenia 2020-05-01 no assertion criteria provided research

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