Submissions for variant NM_000157.4(GBA1):c.254G>A (p.Gly85Glu)

dbSNP: rs77829017

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781409	SCV000919415	pathogenic	Gaucher disease	2017-09-21	criteria provided, single submitter	clinical testing	Variant summary: The GBA c.254G>A (p.Gly85Glu) variant involves the alteration of a conserved nucleotide, resulting in a missense change. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/246122 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant has been identified in numerous patients diagnosed with Gaucher disease Type 1, as a homozygous and compound heterozygous allele, and is a common Gaucher disease allele in East Asian populations (Jeong_2011). One study reported the GBA enzyme activity levels in compound heterozygous patients to be ~10-20% of normal levels (Choi_2015). In addition, multiple reputable databases/clinical diagnostic laboratory have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000781409	SCV001422685	pathogenic	Gaucher disease	2020-01-15	criteria provided, single submitter	curation	The p.Gly85Glu variant in GBA has been reported in at least 15 Korean individuals with Gaucher disease (PMID: 22375149, 20729108, 30764785) and has been identified in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs77829017). 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: 4296) as pathogenic by OMIM. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Gaucher disease based on low glucocerebrosidase activity consistent with disease (PMID: 22375149, 30764785). The presence of this variant in 2 affected homozygotes and in combination with reported pathogenic variants in 9 individuals with Gaucher disease increases the likelihood that the p.Gly85Glu variant is pathogenic (VariationID: 4288, 4301, 65570, 4328, 4297; PMID: 22375149, 20729108, 30764785). 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 compound heterozygotes in combination with pathogenic variants and the phenotype of patients with the variant being highly specific for Gaucher disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4 (Richards 2015).
GeneDx	RCV004589496	SCV005080512	pathogenic	not provided	2023-12-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G46E); This variant is associated with the following publications: (PMID: 32658388, 37530313, 29869463, 22375149, 30764785, 20729108, 33176831, 24904648, 8829654, 33301762)
OMIM	RCV000004532	SCV000024706	pathogenic	Gaucher disease type I	1996-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000781409	SCV001454757	pathogenic	Gaucher disease	2020-09-16	no assertion criteria provided	clinical testing
GeneReviews	RCV000781409	SCV002586405	not provided	Gaucher disease		no assertion provided	literature only