Submissions for variant NM_014000.3(VCL):c.2006G>A (p.Arg669Gln)

gnomAD frequency: 0.00003  dbSNP: rs759771302

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000704837	SCV000364935	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.
Invitae	RCV000704837	SCV000833807	uncertain significance	Dilated cardiomyopathy 1W	2023-05-24	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 669 of the VCL protein (p.Arg669Gln). This variant is present in population databases (rs759771302, gnomAD 0.002%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 300793). This variant has not been reported in the literature in individuals affected with VCL-related conditions.
GeneDx	RCV001548587	SCV001768525	uncertain significance	not provided	2021-04-26	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 300793; Landrum et al., 2016)
New York Genome Center	RCV002467726	SCV002764480	uncertain significance	Dilated cardiomyopathy 1W; Hypertrophic cardiomyopathy 15	2021-12-20	criteria provided, single submitter	clinical testing	The heterozygous c.2006G>A (p.Arg669Gln) missense variant identified in the VCL gene has not been reported in affected individuals in the literature. The variant has 0.00001315 allele frequency in the gnomAD(v3) database (2 out of 152046 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. This variant has been reported in the ClinVar database as a variant of uncertain significance [Variation ID: 300793]. The variant affects a conserved residue and multiple in silico prediction tools provide conflicting predictions about potential pathogenicity ofthis variant (CADD score = 29.8, REVEL score = 0.179). Based on the available evidence, the heterozygous c.2006G>A (p.Arg669Gln) missense variant identified inthe VCL gene is reported as a Variant of Uncertain Significance.
Ambry Genetics	RCV003165817	SCV003871840	uncertain significance	Cardiovascular phenotype	2022-12-01	criteria provided, single submitter	clinical testing	The p.R669Q variant (also known as c.2006G>A), located in coding exon 14 of the VCL gene, results from a G to A substitution at nucleotide position 2006. The arginine at codon 669 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Dept of Medical Biology, Uskudar University	RCV003318374	SCV004022088	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PM2