ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.2969C>T (p.Ala990Val) (rs150595117)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000243207 SCV000318056 uncertain significance Cardiovascular phenotype 2016-07-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000515262 SCV000611525 uncertain significance Dilated cardiomyopathy 1W; Familial hypertrophic cardiomyopathy 15 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000038820 SCV000236478 uncertain significance not specified 2017-02-06 criteria provided, single submitter clinical testing The A990V variant of uncertain significance in the VCL gene has been reported in one individual with anthracycline-associated cardiomyopathy (AACM) (Wasielewski et al., 2014). This variant was found to segregate in three other individuals in this family with AACM, DCM, or SCD (Wasielewski et al., 2014). A990V has also been reported in two additional unrelated individuals with a personal and family history of DCM; however, one of these individuals was also found to harbor several variants in the TTN gene (Pugh et al., 2014). Furthermore, this variant has also been identified independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data is limited for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. A990V has also been reported as variant of uncertain significance in ClinVar by two other clinical laboratories (ClinVar SCV000062498.4, SCV000318056.1; Landrum et al., 2016) and was not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the A990V variant is a conservative amino acid substitution, which may not impact secondary protein structure as these residues share similar properties. Moreover, no missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000539097 SCV000645862 uncertain significance Dilated cardiomyopathy 1W 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 990 of the VCL protein (p.Ala990Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs150595117, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a family affected with anthracycline-associated cardiomyopathy (PMID: 25332820), and in an individual affected with dilated cardiomyopathy that also carried a VUS in TTN (PMID: 24503780).  ClinVar contains an entry for this variant (Variation ID: 45603). 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: "Probably Damaging"; Align-GVGD: "Class  C0"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038820 SCV000062498 uncertain significance not specified 2012-07-30 criteria provided, single submitter clinical testing The Ala990Val variant in VCL has been identified in 4/8600 European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS, dbSNP rs150595117). Computational analyses (biochemica l amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not pr ovide strong support for or against an impact to the protein. Additional informa tion is needed to fully assess the clinical significance of this variant.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786265 SCV000925016 uncertain significance not provided 2017-06-26 no assertion criteria provided provider interpretation The variant has been seen in one patient with idiopathic DCM at our center. Testing was performed at Invitae. Given the weak case data, weak segregation data, and higher frequency in population databases than expected, 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"). The variant has been seen in 1 case of DCM and 1 case of chemotherapy-induced cardiomyopathy (aACM). The patient with DCM had a different likely pathogenic variant. There is weak case data. There is weak segregation data provided in the chemotherapy-induced cardiomyopathy family. Pugh et al (2014) reported this variant in a 2yo with DCM. The patient also harbored a truncating variant in TTN, which was called likely pathogenic (by LMM at time of publication). Wasielewski et al (2014) reported the variant in a patient with anthracycline-associated cardiomyopathy. The text of the paper reports that it segregates with disease in the family, but the pedigree provided is only a two generation pedigree and the only relatives tested were four sisters. The sisters had either aACM, DCM or SCICD. In silico analyses do not agree on the potential impact of this variant on protein function. It should be noted that all of the disease-causing variants in ClinVar are loss of function variants. However, the ExAC variation constraints do show that the VCL gene has fewer missense variants than would be expected by chance. The variant is present in 83 of 138,352 individuals listed 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, Latino, and Ashkenazi descent. Specifically, the variant has been seen in 72 of 63,142 European (Non-finnish individuals) (MAF = 0.057%), 7 of 12,869 Finnish individuals (MAF - 0.027%) The average coverage at that site in gnomAD is 84x for exomes and 30x for genomes.

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