ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1552C>T (p.His518Tyr) (rs573836993)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476577 SCV000553772 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2017-10-04 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 518 of the ACTN2 protein (p.His518Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs573836993, ExAC 0.05%). This variant has not been reported in the literature in individuals with ACTN2-related disease. ClinVar contains an entry for this variant (Variation ID: 412281). 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 C65"). 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769761 SCV000901183 uncertain significance Cardiomyopathy 2015-11-30 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786271 SCV000925024 uncertain significance not provided 2016-05-27 no assertion criteria provided provider interpretation - p.His518Tyr in the ACTN2 gene Given the lack of case data we consider this to be a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen the variant in one individual with LVNC. Testing was done through Invitae. The variant is not reported in the literature. Per the Invitae report, "This sequence change replaces histidine with tyrosine at codon 518 of the ACTN2 protein (p.His518Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. 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 C65")." The variant was absent in 355 controls sequenced by Norton et al., 2011. The variant was reported online in 4 of 60,687 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 5/27/2016). Specifically, the variant was observed in 4 of 4,327 East Asiaactn2n people. The phenotype of those individuals is not publicly available. Another variant affecting the same codon, His518Pro, was also seen in 1 of 8,255 South Asian people. 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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