ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.865A>G (p.Ile289Val) (rs140329381)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236089 SCV000294058 uncertain significance not specified 2017-05-15 criteria provided, single submitter clinical testing The I289V variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. The 1000 Genomes Project reports this variant was observed in 1/694 alleles from individuals of Mixed American ancestry, including one hemizygous individual, indicating it may be a rare benign variant in this population. Although the I289V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position that is conserved across species. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, another pathogenic missense variant in the same residue (I289F) has been reported in the Human Gene Mutation Database in association with Fabry disease (Stenson et al., 2014).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000236089 SCV000539243 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in one patient with Fabry disease. It is present in ExAC with a Max MAF of 0.11% in Latino chrs (with 2 hemizygotes). It's been seen in 1 female with symptoms of Fabry disease. It is classified in ClinVar with 1 star as VUS by GeneDx and Albrecht-Kossel-Institute,Medical University Rostock.
Invitae RCV000209743 SCV000622194 likely benign Fabry disease 2020-12-01 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000209743 SCV000803618 benign Fabry disease 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Benign, for Fabry disease, in X-linked Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:26415523).
Mayo Clinic Laboratories, Mayo Clinic RCV001507540 SCV001713145 uncertain significance not provided 2019-09-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000209743 SCV001735639 uncertain significance Fabry disease 2020-10-06 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 289 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). One study has shown this variant has little impact on GLA enzyme activity (PMID: 26415523). The same study has also shown normal lysoglobotriaosylceramide levels in a few female individuals who underwent biochemical analysis or genetic testing for Fabry Disease (PMID: 26415523). This variant has been identified in 33/205394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Albrecht-Kossel-Institute,Medical University Rostock RCV000209743 SCV000246077 uncertain significance Fabry disease 2014-01-01 no assertion criteria provided research
Albrecht-Kossel-Institute,Medical University Rostock RCV000209181 SCV000246078 drug response Migalastat response 2014-01-01 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000209743 SCV001422797 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided curation The p.Ile289Val variant in GLA has been reported in 4 female individuals with unknown Fabry disease phenotype (PMID: 26415523), and has been identified in 0.096% (27/28054) of Latino chromosomes, including 9 hemizygotes, and 0.032% (6/19042) of African chromosomes, including 2 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140329381). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS by GeneDx, the Laboratory for Molecular Medicine, and the Albrecht-Kossel-Institute, and as likely benign and benign by Invitae and the Swiss Institute of Bioinformatics, respectively (ID: 217400). In vitro functional studies provide some evidence that the p.Ile289Val 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. One additional pathogenic variant, causing a different amino acid change at the same position, p.Ile289Phe, has been reported in association with Fabry disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 21598360, 10666480/Variation ID: 92568). In summary, while the clinical significance of the p.Ile289Val variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, PM5_supporting, BS3_supporting (Richards 2015).

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