Submissions for variant NM_014000.3(VCL):c.1294C>G (p.Leu432Val)

gnomAD frequency: 0.00025  dbSNP: rs144146254

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172503	SCV000051357	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152645	SCV000201982	uncertain significance	not specified	2013-04-12	criteria provided, single submitter	clinical testing	The Leu432Val variant in VCL has not been reported in individuals with cardiomyo pathy, but has been identified in 2/8600 European American chromosomes and 1/440 6 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs .gs.washington.edu/EVS; dbSNP rs144146254). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not prov ide strong support for or against an impact to the protein. Additional informati on is needed to fully assess the clinical significance of this variant.
GeneDx	RCV000172503	SCV000526354	uncertain significance	not provided	2023-02-06	criteria provided, single submitter	clinical testing	Reported in a patient with sudden unexplained death (Lin et al., 2017); At the protein level, in silico analysis supports that this missense variant does not alter protein structure/function; At the mRNA level, in silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29247119, 23861362)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474898	SCV000548805	uncertain significance	Dilated cardiomyopathy 1W	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 432 of the VCL protein (p.Leu432Val). This variant is present in population databases (rs144146254, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29247119). ClinVar contains an entry for this variant (Variation ID: 166543). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272142	SCV002557892	likely benign	Cardiomyopathy	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, null variants have been reported in patients and therefore loss-of-function is speculated (PMID: 32516855). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic carriers have been reported in families with null variants (PMID: 32516855). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to valine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of disease. (SB) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported in a single case of sudden death and in a patient from a cohort which was not pre-selected for personal or family history of arrhythmia, cardiomyopathy or sudden cardiac death. However in the latter case, it is unclear if the patient is clinically affected with any cardiac conditions. Finally, this variant has been classified as VUS by diagnostic laboratories (PMID: 29247119, 23861362; ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002381483	SCV002690916	uncertain significance	Cardiovascular phenotype	2023-07-19	criteria provided, single submitter	clinical testing	The c.1294C>G (p.L432V) alteration is located in exon 10 (coding exon 10) of the VCL gene. This alteration results from a C to G substitution at nucleotide position 1294, causing the leucine (L) at amino acid position 432 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV002272142	SCV003837790	uncertain significance	Cardiomyopathy	2023-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152645	SCV003933898	likely benign	not specified	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: VCL c.1294C>G (p.Leu432Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 282870 control chromosomes (gnomAD), predominantly at a frequency of 0.00035 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1294C>G has been reported in the literature in individuals affected with sudden unexplained death (Lin_2017). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29247119). Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000172503	SCV000925020	uncertain significance	not provided	2016-09-26	no assertion criteria provided	provider interpretation	This variant was identified in one of our patients with a personal and family history of hypertrophic cardiomyopathy (HCM). Testing was done at Invitae. The VCL gene's association with HCM was recently (summer 2016) reviewed by the ClinGen Cardiomyopathy Group, which we belong to. The evidence was considered limited, indicating there is not sufficient evidence that this gene is implicated in HCM to use it clinically. Given the lack of case data and presence in ExAC, 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"). To our knowledge, there is no case data associating this variant with hypertrophic cardiomyopathy. This variant is present in the ClinVar database. Both submitters (Laboratory for Molecular Medicine and the ClinSeq Project) classify this variant as a variant of uncertain significance. In total the variant has not been seen in laboratory controls or published controls. The variant was reported online in 18 of 60699 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 9/26/2016). Specifically, the variant was observed in 17 of 33366 individuals of European (non-Finnish) ancestry and in 1 of 5202 individuals of African ancestry. The phenotype of those individuals is not publicly available. The average coverage at that site in ExAC is 30x. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.