ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.945C>T (p.Asp315=) (rs151208856)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035315 SCV000058963 likely benign not specified 2013-06-17 criteria provided, single submitter clinical testing p.Asp315Asp in exon 6 of GLA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.02% (15/90617) of European chromosomes, including 5 hemizygotes, by the Genome Aggregation Databas e (gnomAD;; dbSNP rs151208856).
GeneDx RCV000035315 SCV000207804 benign not specified 2012-12-11 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.
Invitae RCV000557645 SCV000622196 likely benign Fabry disease 2020-12-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585389 SCV000693354 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035315 SCV000919434 likely benign not specified 2017-11-16 criteria provided, single submitter clinical testing Variant summary: The GLA c.945C>T (p.Asp315Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing (1 tool predicts a decreased affinity for a cryptic donor splice site). ESE finder predicts that this variant may affect a binding site for SF2/ASF. However, these predictions have yet to be confirmed by functional studies. This variant was found in 19/200260 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000166 (15/90617) with 5 hemizygous occurrences, that exceeds the disease prevalence (1/50000), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Taken together, based mainly on the in silico predictions and the observed hemizygous occurrences this variant is classified as likely benign.
Color Health, Inc RCV000557645 SCV001350818 likely benign Fabry disease 2018-10-30 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000557645 SCV000734723 likely benign Fabry disease no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000557645 SCV001422921 likely benign Fabry disease 2020-01-22 no assertion criteria provided curation The c.945C>T variant in GLA has not been previously reported in individuals with Fabry disease, but has been identified in 0.017% (16/92661) of European (non-Finnish) chromosomes, including 6 hemizygotes, and 0.014% (4/28052) of Latino chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD;; dbSNP rs151208856). This variant has been seen in the general population at a greater frequency than expected for Fabry disease and is consistent with a benign role. This variant has been reported in ClinVar as likely benign by the Laboratoy for Molecular Medicine, Invitae, and the University Medical Center Groningen, as benign by GeneDx, and as a VUS by Praxis fuer Humangenetik Tuebingen (Variation ID: 42465). 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_supporting, BP4, BP7 (Richards 2015).

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