Submissions for variant NM_001103.4(ACTN2):c.1918C>T (p.Arg640Cys)

gnomAD frequency: 0.00002  dbSNP: rs769453411

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000351720	SCV000355939	uncertain significance	Dilated cardiomyopathy 1AA	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546797	SCV000636944	uncertain significance	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 640 of the ACTN2 protein (p.Arg640Cys). This variant is present in population databases (rs769453411, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of ACTN2-related conditions (PMID: 26688388, 29247119). ClinVar contains an entry for this variant (Variation ID: 296507). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACTN2 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV002411189	SCV002721397	uncertain significance	Cardiovascular phenotype	2022-06-30	criteria provided, single submitter	clinical testing	The p.R640C variant (also known as c.1918C>T), located in coding exon 16 of the ACTN2 gene, results from a C to T substitution at nucleotide position 1918. The arginine at codon 640 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in sudden death cohorts; however, clinical details were limited (Chanavat V et al. Clin Chim Acta, 2016 Jan;453:80-5; Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:[ePub ahead of print]). Additionally, this variant was detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002504042	SCV002815330	uncertain significance	Dilated cardiomyopathy 1AA; Myopathy, congenital, with structured cores and z-line abnormalities; Myopathy, distal, 6, adult-onset, autosomal dominant	2021-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV003324740	SCV004030623	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	Reported in an individual with DCM and an individual with sudden unexplained death (Chanavat et al., 2016; Lin et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 296507; ClinVar); This variant is associated with the following publications: (PMID: 29247119, 26688388)