ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.754T>A (p.Phe252Ile) (rs381737)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000790654 SCV000232102 pathogenic not provided 2014-04-16 criteria provided, single submitter clinical testing
Invitae RCV000790654 SCV000960225 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with isoleucine at codon 252 of the GBA protein (p.Phe252Ile). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and isoleucine. The frequency data for this variant in the population databases (rs381737, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in several individuals affected with Gaucher disease (PMID: 1301953, 12204005, 17689991) and Parkinson's disease (PMID: 29140481). ClinVar contains an entry for this variant (Variation ID: 4301). This variant is also know as p.Phe213Ile in the literature. Experimental studies have shown that this missense change disrupts enzyme activity in vitro (PMID: 1840477). Variants that disrupt the p.Phe252 amino acid residue in GBA have been observed in affected individuals (PMID: 23430543). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
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 pathologic Gaucher disease 2011-02-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000020158 SCV001422528 pathogenic Gaucher disease 2020-01-22 no assertion criteria provided 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).

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