Submissions for variant NM_000157.4(GBA1):c.764T>A (p.Phe255Tyr)

gnomAD frequency: 0.00001  dbSNP: rs74500255

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498055	SCV000589667	pathogenic	not provided	2024-06-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the variant results in less than 0.5% of wild-type enzyme activity and absence of mature GBA peptide (PMID: 8294487); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(F216Y); This variant is associated with the following publications: (PMID: 1974409, 32618053, 32714263, 37152446, 8294487, 23635853, 30302829)
Baylor Genetics	RCV001004127	SCV001162858	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	RCV001248860	SCV001422529	pathogenic	Gaucher disease	2020-01-14	criteria provided, single submitter	curation	The p.Phe255Tyr variant in GBA has been reported in at least 6 individuals with Gaucher disease, segregated with disease in 3 affected relatives from 1 family, (PMID: 23811968, 24685312, 12587096, 12587096) and has been identified in 0.004% (5/128154) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs74500255). 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: 4298) as pathogenic by OMIM and as likely pathogenic by GeneDx. In vitro functional studies provide some evidence that the p.Phe255Tyr variant may impact protein function (PMID: 8294487). However, these types of assays may not accurately represent biological function. 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 combination with a reported pathogenic variant and in at least 5 individuals with Gaucher disease increases the likelihood that the p.Phe255Tyr variant is pathogenic (VariationID: 4290; PMID: 23635853, 24685312, 23811968, 12587096). 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 combination with other pathogenic variants in affected individuals, functional studies, and co-segregation of the variant with disease. ACMG/AMP Criteria applied: PM3_strong, PM2, PS3_moderate, PP3, PP1 (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV002476925	SCV001652797	pathogenic	Lewy body dementia; Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease perinatal lethal; Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome; Parkinson disease, late-onset	2022-03-16	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001705580	SCV001934283	likely pathogenic	Parkinson disease, late-onset	2020-10-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000498055	SCV002018397	likely pathogenic	not provided	2022-04-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000498055	SCV002496927	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	GBA1: PM3:Strong, PM1, PM2, PS3:Moderate, PP3
AiLife Diagnostics, AiLife Diagnostics	RCV000498055	SCV002502866	likely pathogenic	not provided	2022-02-25	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000498055	SCV002525817	pathogenic	not provided	2021-05-28	criteria provided, single submitter	clinical testing	PS3, PM2, PS4_moderate, PP3, PP4
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001705580	SCV002764720	pathogenic	Parkinson disease, late-onset	2020-09-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001248860	SCV002766107	pathogenic	Gaucher disease	2022-11-02	criteria provided, single submitter	clinical testing	Variant summary: GBA c.764T>A (p.Phe255Tyr) results in a conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249870 control chromosomes. c.764T>A has been reported in the literature in individuals affected with Gaucher Disease (Beutler_1993, DAmore_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal activity (Grace_1994). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000004537	SCV000024711	pathogenic	Gaucher disease type I	1992-04-01	no assertion criteria provided	literature only