ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.1195A>C (p.Asn399His) (rs377228795)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463998 SCV000548795 uncertain significance Dilated cardiomyopathy 1W 2018-10-10 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 399 of the VCL protein (p.Asn399His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs377228795, ExAC 0.05%). This variant has not been reported in the literature in individuals with a VCL-related disease. ClinVar contains an entry for this variant (Variation ID: 408949). 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 and their clinical significance is uncertain. In summary, this variant has uncertain impact on VCL function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786266 SCV000925017 uncertain significance not provided 2017-01-09 no assertion criteria provided provider interpretation Given the limited evidence to associate VCL with dilated cardiomyopathy and the absence of case data available for this variant 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"). There is no case data available for this variant. According to the test report, "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." The asparagine at codon 399 is conserved across species, as are neighboring amino acids. The variant was reported online in 15 of 141,273 individuals (MAF=0.0053%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 7 of 9,468 individuals of East Asian descent (MAF=0.037%), 6 of 15,450 individuals of South Asian descent (MAF=0.019%), 1 of 12,933 individuals of African descent (MAF=0.0039%) and 1 of 18,236 individuals of Latino descent (MAF=0.0027%). Note that the phenotype of the individuals in these datasets is not publicly available. The datasets arecomprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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