ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.8T>C (p.Leu3Pro) (rs150547672)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 Deoxygalactonojirimycin response 2014-01-01 no assertion criteria provided research
Ambry Genetics RCV000622119 SCV000739986 likely benign Cardiovascular phenotype 2016-07-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Intact protein function observed in appropriate functional assay(s)
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000209748 SCV000296877 uncertain significance Fabry disease 2015-10-13 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000209748 SCV000556167 likely benign Fabry disease 2017-09-23 criteria provided, single submitter clinical testing
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; dbSNP rs150547672).

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