ClinVar Miner

Submissions for variant NM_003373.4(VCL):c.1713del (p.Ala573fs) (rs779488376)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000542650 SCV000645848 uncertain significance Dilated cardiomyopathy 1W 2018-12-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala573Hisfs*8) in the VCL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs779488376, ExAC 0.005%). This variant has not been reported in the literature in individuals with a VCL-related disease. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in VCL cause disease. 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000602633 SCV000711970 likely pathogenic Primary dilated cardiomyopathy 2016-04-10 criteria provided, single submitter clinical testing The p.Ala573HisfsX8 variant in VCL has not been previously reported in individua ls with cardiomyopathy though it was identified in 3/121052 of chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). This vari ant is predicted to cause a frameshift, which alters the protein?s amino acid se quence beginning at position 573 and leads to a premature termination codon 8 am ino acids downstream. This alteration is then predicted to lead to a truncated o r absent protein. Current evidence suggests that loss of function of the VCL gen e is associated with dilated cardiomyopathy (DCM). This understanding is based u pon approximately 10 patients with infantile- or childhood- onset DCM that were identified with loss-of-function variants in VCL that also segregated with disea se in five additional family members (LMM, unpublished data). Mouse models have also shown that loss of function of the VCL gene leads to cardiac dysfunction, i ncluding dilated cardiomyopathy (DCM) (Zemljic-Harpf 2007). In summary, although additional studies are required to fully establish its clinical significance, t he p.Ala573HisfsX8 variant is likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. Data from six families tested in our laboratory sugg est over 50% penetrance of the disease in individuals with a loss-of-function va riant.

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