ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.2828_2829del (p.Pro943fs) (rs781036800)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000501801 SCV000598106 uncertain significance Familial hypertrophic cardiomyopathy 15 2016-11-29 criteria provided, single submitter clinical testing
GeneDx RCV000184003 SCV000236497 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing The c.2828_2829delCT variant has not been reported as a disease-causing mutation or as a benign polymorphism. This variant causes a shift in reading frame starting at codon Proline 943, changing it to an Arginine, and creating a premature stop codon at position 9 of the new reading frame, denoted p.Pro943ArgfsX9. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, other truncating mutations associated with cardiomyopathy have not been reported in the VCL gene. With the clinical and molecular information available at this time, we cannot definitively determine if c.2828_2829delCT is a disease-causing mutation or a rare benign variant.
Invitae RCV000537723 SCV000645859 uncertain significance Dilated cardiomyopathy 1W 2017-05-16 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotide from exon 19 of the VCL mRNA (c.2828_2829delCT), causing a frameshift at codon 943. This creates a premature translational stop signal (p.Pro943Argfs*9) and is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs781036800, ExAC 0.05%). This variant has been reported in an individual affected with peripartum cardiomyopathy (PMID: 26735901). ClinVar contains an entry for this variant (Variation ID: 202163). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in VCL cause disease. Therefore, this variant has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000219138 SCV000271292 likely pathogenic Primary dilated cardiomyopathy 2015-11-27 criteria provided, single submitter clinical testing The p.Pro943fs variant in VCL has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 5/10406 of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 781036800). This variant is predicted to cause a frameshift, which alters the pr otein?s amino acid sequence beginning at position 943 and leads to a premature t ermination codon 9 amino acids downstream. Mouse models have shown that loss of function of the VCL gene can lead to DCM (Zemljic-Harpf 2007), although the mode of inheritance associated with such variants in humans is not yet clear. In sum mary, although additional studies are required to fully establish its clinical s ignificance, the p.Pro943fs variant is likely pathogenic.

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