ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1538C>A (p.Thr513Asn) (rs749178520)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457208 SCV000553755 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2016-09-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 513 of the ACTN2 protein (p.Thr513Asn). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs749178520, ExAC 0.003%) but has not been reported in the literature in individuals with a ACTN2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786273 SCV000925027 uncertain significance not provided 2016-11-10 no assertion criteria provided provider interpretation ACTN2 Gene Level Evidence There is limited evidence associating the ACTN2 gene with hypertrophic cardiomyopathy. One family has been reported by the Semsarian group (Chiu et al., 2010) to have linkage to the ACTN2 locus with a LOD score of 2.82 and segregation of Ala119Thr in 7 affected family members in two generations. p.Thr513Asn (c.1538C>A) in the ACTN2 gene (NM_001103.3). See report below. We have seen this variant in a person with HCM. Testing was performed by Invitae. Given the limited evidence linking this gene to HCM and lack of case data associating this variant with disease, we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in the literature as of 11/10/2016. Per the Invitae report, "The threonine residue is highly conserved and there is a small physicochemical difference between threonineband asparagine... Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies." The variant was reported online in 3 of 126,177 individuals (MAF 0.001%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 3 of 56,095 individuals of non-Finnish European descent (AF 0.003%). 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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