ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.947T>C (p.Met316Thr) (rs370757762)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000363438 SCV000355905 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.
Invitae RCV001087580 SCV000553747 likely benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2020-11-11 criteria provided, single submitter clinical testing
GeneDx RCV000603522 SCV000718974 likely benign not specified 2017-11-14 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000620316 SCV000735507 uncertain significance Cardiovascular phenotype 2017-11-15 criteria provided, single submitter clinical testing The p.M316T variant (also known as c.947T>C), located in coding exon 10 of the ACTN2 gene, results from a T to C substitution at nucleotide position 947. The methionine at codon 316 is replaced by threonine, an amino acid with similar properties. Based on data from gnomAD, the C allele has an overall frequency of approximately 0.014% (40/277148) total alleles studied. The highest observed frequency was 0.21% (39/18866) of East Asian alleles.This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786272 SCV000925026 uncertain significance not provided 2016-09-06 no assertion criteria provided provider interpretation p.Met316Thr (c.947T>C) in the ACTN2 gene (NM_001103.3) Given the high allele frequency (0.1%) in individuals matching our patient's ancestry, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per the lab report the variant has not been reported in association with disease. The variant was reported online in 11 of 60705 individuals in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6 Sep 2016). Specifically, the variant was observed in 11 of 4327 (AF 0.001271). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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