Submissions for variant NM_000157.4(GBA1):c.625C>T (p.Arg209Cys)

gnomAD frequency: 0.00001  dbSNP: rs398123532

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179793	SCV000232100	pathogenic	not provided	2012-07-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780284	SCV000917427	pathogenic	Gaucher disease	2017-12-11	criteria provided, single submitter	clinical testing	Variant summary: The GBA c.625C>T (p.Arg209Cys) variant involves the alteration of a conserved nucleotide. 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 3/227084 control chromosomes at a frequency of 0.0000132, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant has been reported in affected individuals in the literature and functional studies have shown completely absent transcript in a patient carrying the variant in the homozygous state (Dominissini_2005). In addition, one other clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV001004133	SCV001162864	pathogenic	Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome		criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000780284	SCV001422956	pathogenic	Gaucher disease	2020-01-13	criteria provided, single submitter	curation	The p.Arg209Cys variant in GBA has been reported in at least 14 individuals with Gaucher disease, segregated with disease in 4 affected relatives from 2 families (PMID: 10369158, 30115580, 12204005, 10796875, 26756743, 28727984, 16329099, 21704274; DOI: 10.13140/RG.2.1.3564.6481), and has been identified in 0.007% (1/14436) of African chromosomes, 0.003% (1/28708) of South Asian chromosomes, and 0.001% (1/103466) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123532). 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: 93455) as pathogenic by EGL Genetic Diagnostics. 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 presence of this variant in two affected homozygotes and in combination with reported pathogenic variants in 4 individuals with Gaucher disease increases the likelihood that the p.Arg209Cys variant is pathogenic (VariationId: 4288, 4290; PMID: 10369158, 30115580, 12204005, 10796875). The phenotype of an individual compound heterozygous for this variant is highly specific for Gaucher disease based on low residual enzyme activity consistent with disease (PMID: 16329099). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg209Pro, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 12204005, 9683600, 10796875). 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, cosegregation of the variant with Gaucher disease, and a patient's phenotype being highly specific for Gaucher disease. ACMG/AMP Criteria applied: PM3_strong, PM2, PP3, PP4, PM5_supporting, PP1 (Richards 2015).
AiLife Diagnostics, AiLife Diagnostics	RCV000179793	SCV002503550	likely pathogenic	not provided	2020-12-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000179793	SCV004228231	pathogenic	not provided	2023-05-17	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3_strong, PS4_moderate
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV004698469	SCV005199940	pathogenic	Gaucher disease type I	2024-08-24	criteria provided, single submitter	clinical testing	A heterozygous variant in exon 6 of the GBA gene that results in the amino acid substitution of Cysteine for Arginine at codon 209 was detected. The observed variant c.625C>T have MAF of 0.0013% in the gnomAD database. The in silico predictions is damaging by MutationTaster, DANN and FATHMM. In summary, the variant meets our criteria to be classified as pathogenic.
Natera, Inc.	RCV000780284	SCV001461744	pathogenic	Gaucher disease	2020-09-16	no assertion criteria provided	clinical testing