ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1930G>A (p.Ala644Thr) (rs146164600)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617742 SCV000736290 uncertain significance Cardiovascular phenotype 2016-08-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769764 SCV000901186 uncertain significance Cardiomyopathy 2017-08-18 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678697 SCV000804859 uncertain significance Tetralogy of Fallot 2017-02-27 no assertion criteria provided clinical testing
GeneDx RCV000766340 SCV000235694 uncertain significance not provided 2017-08-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTN2 gene. The A644T variant has previously been reported in one proband with HCM and was absent from 520 control chromosomes (Chiu et al., 2010). However, this variant was also identified in unaffected family members (Chiu et al., 2010). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to insufficient participation by informative family members. The A644T variant has been observed in 40/126488 (0.03%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Nevertheless, the A644T 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 where only amino acids with similar properties to alanine (A) are tolerated across species. Lastly, a majority of in silico analysis algorithms predict this variant is probably damaging to the protein structure/function.
Invitae RCV000228537 SCV000285863 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 644 of the ACTN2 protein (p.Ala644Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs146164600, ExAC 0.04%). This variant has been reported in the literature in an individual affected with hypertrophic cardiomyopathy, but also in unaffected relatives (PMID: 20022194) and in an individual affected with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 43920). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036890 SCV000060545 uncertain significance not specified 2010-06-14 criteria provided, single submitter clinical testing The Ala644Thr variant has been reported in one proband with HCM. Although the va riant was absent from 520 control chromosomes, the authors classified it as ?ben ign? due to its presence in unaffected family members. However, no clinical deta ils are available (Chiu 2009). Alanine (Ala) at position 644 is not completely c onserved across different species (frog carries a glycine), reducing the likelih ood that a change is pathogenic. In addition, this individual has a diagnosis o f DCM, while the proband tested by Chiu 2009 was diagnosed with HCM. Provided th at the diagnosis of primary DCM has been firmly established, the presence of a v ariant in HCM and DCM probands reduces the likelihood that it is pathogenic as t he two cardiomyopathies are caused by different defects at the cellular level. In summary, the clinical significance of this variant cannot be determined witho ut additional studies.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000624002 SCV000740534 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-10-11 criteria provided, single submitter clinical testing

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