ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.681T>G (p.Asn227Lys) (rs381418)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079353 SCV000111223 pathogenic not provided 2017-05-26 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004130 SCV001162861 pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease type 3C criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001249030 SCV001422960 likely pathogenic Gaucher disease 2020-01-29 no assertion criteria provided curation The p.Asn227Lys variant in GBA has been reported in 5 individuals with Gaucher disease (PMID: 9683600, 23719189, 10649495, 25435509, 27872820) and has been identified in 0.002% (2/113716) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs381418). Please note that 1 additional individual in gnomAD has this change in phase with an additional nucleotide change, resulting in a multinucleotide variant (p.Asn227Arg). 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: 93458) as pathogenic by EGL Genetic Diagnostics. The phenotype of individuals compound heterozygous for this variant is highly specific for Gaucher disease based on null or very low beta-glucosidase levels consistent with disease (PMID: 27872820, 9683600). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Asn227Ile, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 26743617, 24022302). The presence of this variant in combination with reported pathogenic variants and in 3 individuals with Gaucher disease increases the likelihood that the p.Asn227Lys variant is pathogenic (VariationID: 4288, 4290; PMID: 9683600, 23719189, 27872820). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PM5_supporting, PP4 (Richards 2015).

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