ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.8T>C (p.Leu3Pro) (rs150547672)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035313 SCV000058961 benign not specified 2015-07-29 criteria provided, single submitter clinical testing p.Leu3Pro in exon 1 of GLA: This variant is not expected to have clinical signif icance because it has been identified in 0.3% (26/8444) of African chromosomes i ncluding 4 hemizygous males by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org/; dbSNP rs150547672).
GeneDx RCV000035313 SCV000207806 benign not specified 2017-01-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000209748 SCV000296877 uncertain significance Fabry disease 2015-10-13 criteria provided, single submitter clinical testing
Invitae RCV000209748 SCV000556167 likely benign Fabry disease 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622119 SCV000739986 likely benign Cardiovascular phenotype 2018-09-27 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Subpopulation frequency in support of benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035313 SCV000917448 likely benign not specified 2018-07-30 criteria provided, single submitter clinical testing Variant summary: GLA c.8T>C (p.Leu3Pro) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 200269 control chromosomes, predominantly observed within the African subpopulation at a frequency of 0.0029 in the gnomAD database, including 11 hemizygotes. This frequency is not higher than expected for a pathogenic variant in GLA causing Cardiomyopathy (0.0029 vs 0.0071). c.8T>C has been reported in the literature in individuals affected with Fabry disease (Lukas 2016), however in this study, authors found normal biomarker levels in these individuals. Experimental evidence evaluating an impact on protein function also showed normal (or somewhat elevated) activity for the variant protein (Lukas 2016). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with two laboratories classifying as "benign", two classifying as "likely benign", and one classifying as "VUS". Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000209748 SCV001357613 likely benign Fabry disease 2018-11-11 criteria provided, single submitter clinical testing
Albrecht-Kossel-Institute,Medical University Rostock RCV000209748 SCV000246017 uncertain significance Fabry disease 2014-01-01 no assertion criteria provided research
Albrecht-Kossel-Institute,Medical University Rostock RCV000209183 SCV000246018 drug response Migalastat response 2014-01-01 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000209748 SCV001423100 likely benign Fabry disease 2020-01-22 no assertion criteria provided curation The p.Leu3Pro variant in GLA has not been previously reported in individuals with Fabry disease, and has been identified in 0.32% (61/19010) of African chromosomes, including 11 hemizygotes, and 0.0036% (1/28047) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150547672). This variant has been reported in ClinVar as benign by the Laboratory for Molecular Medicine (Partners Healthcare) and GeneDx, as likely benign by Invitae and Ambry Genetics, and as a VUS by Albrecht-Kossel-Institute (Medical University Rostock) and the Division of Genomic Diagnostics (The Children's Hospital of Philadelphia) (ID:42464). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015).

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