ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.2875A>C (p.Asn959His) (rs758969419)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244158 SCV000319539 uncertain significance Cardiovascular phenotype 2015-04-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000472333 SCV000548799 uncertain significance Dilated cardiomyopathy 1W 2018-07-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 959 of the VCL protein (p.Asn959His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs758969419, ExAC 0.001%). This variant has not been reported in the literature in individuals with VCL-related disease. ClinVar contains an entry for this variant (Variation ID: 263962). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 RCV000825048 SCV000966247 uncertain significance not specified 2018-10-08 criteria provided, single submitter clinical testing The p.Asn959His variant in VCL has been reported in one individual with dilated cardiomyopathy (Schymanski 2017). It has also been reported as a variant of unce rtain significance in ClinVar (Variation ID# 263962). This variant has been iden tified in 0.004% (1/24037) of African chromosomes by the Genome Aggregation Data base (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Asn959His varian t is uncertain. ACMG/AMP Criteria applied: PM2_Supporting.

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