ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.1294C>G (p.Leu432Val) (rs144146254)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172503 SCV000051357 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000152645 SCV000201982 uncertain significance not specified 2013-04-12 criteria provided, single submitter clinical testing The Leu432Val variant in VCL has not been reported in individuals with cardiomyo pathy, but has been identified in 2/8600 European American chromosomes and 1/440 6 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs; dbSNP rs144146254). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not prov ide strong support for or against an impact to the protein. Additional informati on is needed to fully assess the clinical significance of this variant.
GeneDx RCV000172503 SCV000526354 uncertain significance not provided 2018-12-21 criteria provided, single submitter clinical testing The L432V variant of uncertain significance in the VCL gene has been reported reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013). Additionally, this variant has been reported in a patient with sudden unexplained death (Lin et al., 2017). The L432V variant is observed in 43/277218 (0.02%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The L432V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000474898 SCV000548805 uncertain significance Dilated cardiomyopathy 1W 2017-07-20 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 432 of the VCL protein (p.Leu432Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs144146254, ExAC 0.03%) but has not been reported in the literature in individuals with a VCL-related disease. ClinVar contains an entry for this variant (Variation ID: 166543). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000172503 SCV000925020 uncertain significance not provided 2016-09-26 no assertion criteria provided provider interpretation This variant was identified in one of our patients with a personal and family history of hypertrophic cardiomyopathy (HCM). Testing was done at Invitae. The VCL gene's association with HCM was recently (summer 2016) reviewed by the ClinGen Cardiomyopathy Group, which we belong to. The evidence was considered limited, indicating there is not sufficient evidence that this gene is implicated in HCM to use it clinically. Given the lack of case data and presence in ExAC, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). To our knowledge, there is no case data associating this variant with hypertrophic cardiomyopathy. This variant is present in the ClinVar database. Both submitters (Laboratory for Molecular Medicine and the ClinSeq Project) classify this variant as a variant of uncertain significance. In total the variant has not been seen in laboratory controls or published controls. The variant was reported online in 18 of 60699 individuals in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 9/26/2016). Specifically, the variant was observed in 17 of 33366 individuals of European (non-Finnish) ancestry and in 1 of 5202 individuals of African ancestry. The phenotype of those individuals is not publicly available. The average coverage at that site in ExAC is 30x. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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