ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.1196G>C (p.Trp399Ser) (rs782449839)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000209559 SCV000622181 uncertain significance Fabry disease 2019-10-08 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with serine at codon 399 of the GLA protein (p.Trp399Ser). The tryptophan residue is moderately conserved and there is a large physicochemical difference between tryptophan and serine. This variant is present in population databases (rs782449839, ExAC 0.1%). This variant has been reported in individuals affected with late-onset Fabry disease (PMID: 26415523, 28253518). ClinVar contains an entry for this variant (Variation ID: 217414). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Gharavi Laboratory,Columbia University RCV000782201 SCV000920678 uncertain significance not provided 2018-09-16 criteria provided, single submitter research
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256949 SCV001433478 uncertain significance Familial hypertrophic cardiomyopathy 1 2020-05-18 criteria provided, single submitter clinical testing
Albrecht-Kossel-Institute,Medical University Rostock RCV000209559 SCV000246105 likely pathogenic Fabry disease 2014-01-01 no assertion criteria provided research
Albrecht-Kossel-Institute,Medical University Rostock RCV000208881 SCV000246106 drug response Deoxygalactonojirimycin response 2014-01-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000782201 SCV000925091 uncertain significance not provided 2017-11-01 no assertion criteria provided provider interpretation p.Trp399Ser (c.1196G>C) in GLA, Exon 7, (NM_000169.2; chrX-100652891-C-G) SCICD Classification: variant of uncertain significance, probably benign based on the allele frequency. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data (not including our patient): Reported with Fabry. Per the lab report "This variant has been reported in individuals affected with late-onset Fabry disease (PMID: 26415523,)." Population data: Highest MAF in South Asian population: 0.07835% in gnomAD exomes (ExAC)
Broad Institute Rare Disease Group,Broad Institute RCV000209559 SCV001422792 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided curation The p.Trp399Ser variant in GLA has been reported in at least 3 individuals with Fabry disease (PMID: 26415523,28253518, 29794742), and has been identified in 0.08% (15/19080) of South Asian chromosomes, including 7 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs782449839). This variant has also been reported in ClinVar as likely pathogenic by Albrecht-Kossel-Institute (Medical University Rostock) and a VUS by Invitae (ID: 217414). In vitro functional studies provide some evidence that the p.Trp399Se variant may not impact protein function (PMID: 26415523). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of individuals hemizygous for this variant is highly specific for Fabry disease based on the classical phenotype which is consistent with disease (PMID: 26415523, 28253518, 28728877). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS1, PP4, PS4_supporting, BS3_supporting (Richards 2015).

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