Submissions for variant NM_014000.3(VCL):c.2468G>A (p.Arg823Gln)

gnomAD frequency: 0.00006  dbSNP: rs759202535

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208526	SCV000264317	uncertain significance	Primary familial hypertrophic cardiomyopathy	2015-09-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645320	SCV000767063	uncertain significance	Dilated cardiomyopathy 1W	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 823 of the VCL protein (p.Arg823Gln). This variant is present in population databases (rs759202535, gnomAD 0.009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221, 32880476). ClinVar contains an entry for this variant (Variation ID: 222889). 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 disruptive. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000994451	SCV001147983	uncertain significance	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000645320	SCV001260514	uncertain significance	Dilated cardiomyopathy 1W	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002444838	SCV002733898	uncertain significance	Cardiovascular phenotype	2024-01-02	criteria provided, single submitter	clinical testing	The p.R823Q variant (also known as c.2468G>A), located in coding exon 17 of the VCL gene, results from a G to A substitution at nucleotide position 2468. The arginine at codon 823 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485364	SCV002785136	uncertain significance	Dilated cardiomyopathy 1W; Hypertrophic cardiomyopathy 15	2021-07-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987451	SCV004803457	likely benign	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: VCL c.2468G>A (p.Arg823Gln) 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 4.6e-05 in 282852 control chromosomes, predominantly at a frequency of 8.5e-05 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 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2468G>A has been reported in the literature in individuals affected with Dilated cardiomyopathy (Mazzarotto_2020, Verdonschot_2020). These reports do 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 publications have been ascertained in the context of this evaluation (PMID: 31983221, 32880476). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000994451	SCV005080803	uncertain significance	not provided	2024-02-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Reported in association with dilated cardiomyopathy (DCM) in published literature; however, additional cardiogenetic variants were reported in some cases (PMID: 30847666, 32880476, 31983221); This variant is associated with the following publications: (PMID: 31983221, 32880476, 30847666)
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000994451	SCV005198982	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000994451	SCV001740724	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000994451	SCV001917896	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000994451	SCV001959565	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000994451	SCV001972965	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947683	SCV004766040	uncertain significance	VCL-related disorder	2024-01-03	no assertion criteria provided	clinical testing	The VCL c.2468G>A variant is predicted to result in the amino acid substitution p.Arg823Gln. This variant was reported in multiple individuals with dilated cardiomyopathy (File S2, van Lint et al. 2019. PubMed ID: 30847666; Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221; Table S4, Verdonschot et al. 2020. PubMed ID: 32880476). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/222889/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.