Submissions for variant NM_000157.4(GBA1):c.754T>A (p.Phe252Ile)

gnomAD frequency: 0.00001  dbSNP: rs381737

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790654	SCV000232102	pathogenic	not provided	2014-04-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000790654	SCV000960225	pathogenic	not provided	2023-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 252 of the GBA protein (p.Phe252Ile). This variant is present in population databases (rs381737, gnomAD 0.01%). This missense change has been observed in individual(s) with Gaucher disease and/or Parkinson's disease (PMID: 1301953, 12204005, 17689991, 29140481). This variant is also known as p.Phe213Ile. ClinVar contains an entry for this variant (Variation ID: 4301). 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: 1840477). This variant disrupts the p.Phe252 amino acid residue in GBA. Other variant(s) that disrupt this residue have been observed in individuals with GBA-related conditions (PMID: 23430543), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020158	SCV001337956	pathogenic	Gaucher disease	2020-01-18	criteria provided, single submitter	clinical testing	Variant summary: GBA c.754T>A (p.Phe252Ile) results in a non-conservative amino acid change located in the Glycosyl hudrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251488 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GBA causing Gaucher Disease (4.4e-05 vs 0.005), allowing no conclusion about variant significance. c.754T>A has been reported in the literature in multiple individuals from diverse ethnic backgrounds affected with Gaucher Disease, example, Japanese (Kawame_1991), English (He_1992), Italian (Filocamo_1992), Thai (Suwannarat_2007), and Indian (Sheth_2019), in addition to patients affected with Parkinson's disease (example, Trinh_2019). These data indicate that the variant is very 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 <10% of normal activity in transient expression of Glucocerebrosidase activity in transfected COS-1 cells (example, Kawame_1991). 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 using overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000020158	SCV001422528	pathogenic	Gaucher disease	2020-01-22	criteria provided, single submitter	curation	The p.Phe2252Ile variant in GBA has been reported in at least 17 individuals with Gaucher disease and has been identified in 0.010% (2/19954) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs381737). 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: 4301) as pathogenic by EGL Genetic Diagnostics and OMIM. In vitro functional studies provide some evidence that the p.Phe252Ile variant may impact protein function (PMID: 15276648). However, these types of assays may not accurately represent biological function. Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The Phe at position 252 is highly conserved in mammals and evolutionary distant species, but 1 mammal (Chimp) carries an Ile, raising the possibility that this change at this position may be tolerated. The presence of this variant in 4 affected homozygotes and in combination with reported pathogenic variants in 8 individuals with Gaucher disease increases the likelihood that the p.Phe252Ile variant is pathogenic (VariationID: 4296, 4288, 4327, 4328; PMID: 17689991, 20729108, 15954102, 30949558, 30764785, 29685539). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Gaucher disease based on significantly reduced levels of beta-glucosidase in patient leukocytes consistent with disease (PMID: 17689991, 30764785, 15954102). 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 vitro functional studies, and the phenotype of individuals with the variant being highly specific for Gaucher disease. ACMG/AMP Criteria applied: PM3_very-strong, PS3_moderate, PM2_supporting, PP4 (Richards 2015).
GeneDx	RCV000790654	SCV001875186	pathogenic	not provided	2021-02-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant results in deficient beta-glucocerebrosidase activity (Kawame et al., 1991; Kim et al., 2020); Also described in past literature as p.F213I using alternate nomenclature; This variant is associated with the following publications: (PMID: 32677286, 33176831, 27802905, 15954102, 15276648, 23430543, 20301446, 30764785, 30949558, 19830760, 31637888, 30537300, 12204005, 25435509, 25875285, 29699937, 14984463, 16720474, 17689991, 1840477, 1301953, 29685539, 29140481, 20729108)
Ambry Genetics	RCV004018559	SCV002754807	likely pathogenic	not specified	2018-02-19	criteria provided, single submitter	clinical testing	The p.F252I variant (also known as c.754T>A, p.F213I, and c.3548T>A), located in coding exon 6 of the GBA gene, results from a T to A substitution at nucleotide position 754. The phenylalanine at codon 252 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been detected in individuals with confirmed diagnoses of Gaucher disease, in both homozygous and compound heterozygous states (Suwannarat P et al. Blood Cells Mol. Dis. Aug;39:348-52; Ortiz-Cabrera NV et al. Mol Genet Metab Rep, 2016 Dec;9:79-85; Santamaria R et al. Hum. Mutat., 2008 Jun;29:E58-67; Tang NL et al. Hum. Mutat., 2005 Jul;26:59-60; Kawame H et al. Am. J. Hum. Genet., 1991 Dec;49:1378-80; Latham TE et al. DNA Cell Biol.;10:15-21). In addition, in one study authors showed that, when this alteration was transfected into COS-1 cells, the glucosidase activity failed to increase as efficiently as normal cDNA (Kawame H et al. Am. J. Hum. Genet., 1991 Dec;49:1378-80). Of note, this alteration has also been detected in GBA pseudogene. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002482827	SCV002787521	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	2021-10-29	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004820816	SCV005442027	pathogenic	Lewy body dementia	2024-12-19	criteria provided, single submitter	clinical testing
OMIM	RCV000004540	SCV000024714	pathogenic	Gaucher disease type III	1992-01-01	no assertion criteria provided	literature only
OMIM	RCV000004541	SCV000024715	pathogenic	Gaucher disease type II	1992-01-01	no assertion criteria provided	literature only
OMIM	RCV000004542	SCV000024716	pathogenic	Gaucher disease type I	1992-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000020158	SCV000040485	not provided	Gaucher disease		no assertion provided	literature only
Natera, Inc.	RCV000020158	SCV002086471	pathogenic	Gaucher disease	2017-05-06	no assertion criteria provided	clinical testing