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, 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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