ClinVar Miner

Submissions for variant NM_001103.4(ACTN2):c.2054T>C (p.Ile685Thr)

gnomAD frequency: 0.00001  dbSNP: rs1057523250
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000418962 SCV000531242 uncertain significance not provided 2016-08-22 criteria provided, single submitter clinical testing A novel variant of uncertain significance has been identified in the ACTN2 gene. The I685T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I685T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014). Furthermore, to our knowledge no studies have been performed to determine the functional effect of the I685T variant.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Labcorp Genetics (formerly Invitae), Labcorp RCV001060120 SCV001224784 likely benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2025-01-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002418315 SCV002724478 uncertain significance Cardiovascular phenotype 2022-06-16 criteria provided, single submitter clinical testing The p.I685T variant (also known as c.2054T>C), located in coding exon 17 of the ACTN2 gene, results from a T to C substitution at nucleotide position 2054. The isoleucine at codon 685 is replaced by threonine, an amino acid with similar properties. 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 RCV002506061 SCV002815842 uncertain significance Dilated cardiomyopathy 1AA; Myopathy, congenital, with structured cores and z-line abnormalities; Myopathy, distal, 6, adult-onset, autosomal dominant 2021-09-23 criteria provided, single submitter clinical testing

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