Submissions for variant NM_000157.4(GBA1):c.1297G>T (p.Val433Leu)

gnomAD frequency: 0.00001  dbSNP: rs80356769

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020148	SCV000697579	pathogenic	Gaucher disease	2017-05-08	criteria provided, single submitter	clinical testing	Variant summary: The GBA c.1297G>T (p.Val433Leu) variant (alternatively also known as V394L) involves the alteration of a conserved nucleotide, is located in TIM-barrel domain of the protein (InterPro) and is predicted to be damaging by 2/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 4/120330 control chromosomes from ExAC at a frequency of 0.0000332, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant is one of the common pathogenic variants in Ashkenazi population (Beutler_1993, Elstein_2005, and Orenstein_2014). In a genotype-phenotype study (Elstein_2005) that included N370S/V394L compound heterozygotes, most of the patients had mild disease; only 8 patients required specific enzyme therapy, none was splenectomized. Only 3 patients had skeletal involvement, but other baseline parameters were very diverse. Authors note that although genotype-phenotype correlation in this case may be difficult, because the V394L mutation when seen in a compound heterozygote with a null allele results in neuronopathic disease, one cannot conclude that this mutation is protective of neuronopathic disease. Patients carrying this variant in homozygous state have not been reported so far. Functional studies in insect cell system and mouse models have shown that the variant leads to severe decrease in enzymatic activity (11-15 % of wildtype activity) and neurological phenotype is recapitulated in transgenic mice carrying this variant (Grace_1994, Liou_2006, Xu_2011). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762854	SCV000893214	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	2021-11-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004115	SCV001162846	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
Myriad Genetics, Inc.	RCV000004521	SCV001193973	likely pathogenic	Gaucher disease type I	2019-12-11	criteria provided, single submitter	clinical testing	NM_001005741.2(GBA):c.1297G>T(V433L, aka V394L) is classified as likely pathogenic in the context of Gaucher disease and can be associated with Type 1, 2 or 3. Sources cited for classification include the following: PMID 10796875, 8294487, 16293621, 2508065, 21257328 and 12595585. Classification of NM_001005741.2(GBA):c.1297G>T(V433L, aka V394L) 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382044	SCV001580650	pathogenic	not provided	2024-02-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 433 of the GBA protein (p.Val433Leu). This variant is present in population databases (rs80356769, gnomAD 0.07%). This missense change has been observed in individual(s) with Gaucher disease and Parkinson's disease (PMID: 10714667, 24685312, 25653295, 27271787). This variant is also known as p.Val394Leu or V394L. ClinVar contains an entry for this variant (Variation ID: 4292). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GBA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 14578207, 21257328). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001836694	SCV001652798	pathogenic	Parkinson disease, late-onset	2021-05-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001382044	SCV002024186	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing
OMIM	RCV000004520	SCV000024694	pathogenic	Gaucher disease type III	1991-01-01	no assertion criteria provided	literature only
OMIM	RCV000004521	SCV000024695	pathogenic	Gaucher disease type I	1991-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000020148	SCV000040475	not provided	Gaucher disease		no assertion provided	literature only
Natera, Inc.	RCV000020148	SCV002086455	pathogenic	Gaucher disease	2017-03-17	no assertion criteria provided	clinical testing