ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.562C>T (p.Arg188Ter) (rs397517244)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183988 SCV000236482 uncertain significance not provided 2013-09-18 criteria provided, single submitter clinical testing p.Arg188Stop (CGA>TGA): c.562 C>T in exon 5 of the VCL gene (NM_014000.2).The Arg188Stop mutation in the VCL gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg188Stop was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Arg188Stop variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Nevertheless, no nonsense or frameshift disease-causing mutations in the VCL gene have been reported in association with cardiomyopathy.With the clinical and molecular information available at this time, we cannot definitively determine if Arg188Stop is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Invitae RCV000645310 SCV000767053 uncertain significance Dilated cardiomyopathy 1W 2017-09-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg188*) in the VCL gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 45615). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in VCL cause disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038833 SCV000062511 likely pathogenic Primary dilated cardiomyopathy 2010-06-17 criteria provided, single submitter clinical testing The Arg188X variant has not been reported in the literature. However, it leads t o a premature stop at codon 188. This alteration is predicted to lead to a trunc ated or absent protein. A pathogenic role of nonsense variants in the VCL gene i s supported by one study reported a reduction in VCL expression in an individual with cardiomyopathy carrying a VCL variant (Vasile 2006). In addition, our labo ratory has identified nonsense variants in VCL in 4/14 cardiomyopathy probands. In summary, the Arg188X variant is likely to be pathogenic.

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