ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1031A>G (p.Asn344Ser) (rs886046206)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000560337 SCV000636925 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2017-07-20 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 344 of the ACTN2 protein (p.Asn344Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ACTN2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786084 SCV000924718 uncertain significance not provided 2017-11-30 no assertion criteria provided provider interpretation p.Asn344Ser (c.1031A>G) in exon 10 of the ACTN2 gene (NM_001103.3; chr1-236902756-A-G) SCICD Classification: variant of uncertain significance based on limited data to associate this gene with disease and lack of case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: ACTN2: We recently (2016) reviewed ACTN2's relationship with hypertrophic cardiomyopathy (HCM) in the ClinGen Cardiovascular Working Group and concluded that there is limited evidence supporting it as a disease gene for HCM. The ACNT2 gene encodes a muscle-specific alpha-actinin that is expressed in both skeletal and cardiac muscle. Alpha-actinin is localized in the Z-disc where it helps anchor myofibrillar actin filaments. Heterozygous variants in ACTN2 have been reported in associated with DCM, though they seem to represent only a small number of cases without strong segregation data or an animal model. LMM shared that they feel there is stronger evidence for ACTN2 as an HCM gene than DCM and for now they are handling these variants as ones of uncertain significance until more data is available. The Semsarian group has also reported ACTN2 as a putative HCM gene (Chiu et al 2010). In a family with HCM they found linkage to the ACTN2 locus with a LOD score of 2.82. Sequencing identified p.Ala119Thr in 7 affected family members in two generations. As such, ACTN2 remains a gene with unclear significance to HCM or DCM. Case data (not including our patient): ClinVar: not present Cases in the literature: none reported Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align- GVGD: "Class C45")." Conservation data: The asparagine at codon 344 is almost completely conserved across species (until zebrafish). Neighboring amino acids are completely conserved. Nearby pathogenic variants at this codon or neighboring codons: variant at the same codon (p.Asn344Thr) listed as variant of uncertain significance by Illumina clinical laboratories. Nearby variants are listed in ClinVar but are listed as variants of uncertain significance. Population data: Highest MAF in European (Finnish) population: 0.004484%. The variant was reported online in 1 of 123,130 individuals in the Genome Aggregation Consortium Dataset (gnomAD;, which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 11,150 individuals of European (Finnish) descent (MAF=0.004484%). 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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