Submissions for variant NM_001103.4(ACTN2):c.1930G>A (p.Ala644Thr)

gnomAD frequency: 0.00014  dbSNP: rs146164600

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
GeneDx	RCV000766340	SCV000235694	uncertain significance	not provided	2023-07-14	criteria provided, single submitter	clinical testing	Reported in patients with cardiomyopathy in the published literature (Chiu et al., 2010; Pugh et al., 2014; Lombardi et al., 2020; Sepp et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 32527005, 20022194, 35626289, 28771489)
Invitae	RCV000228537	SCV000285863	likely benign	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617742	SCV000736290	uncertain significance	Cardiovascular phenotype	2022-09-13	criteria provided, single submitter	clinical testing	The p.A644T variant (also known as c.1930G>A), located in coding exon 16 of the ACTN2 gene, results from a G to A substitution at nucleotide position 1930. The alanine at codon 644 is replaced by threonine, an amino acid with some similar properties. This alteration was reported in an individual with hypertrophic cardiomyopathy (HCM), but was also in unaffected family members. However, clinical details were not provided (Chiu C et al. J. Am. Coll. Cardiol., 2010 Mar;55:1127-35). This alteration was also described in one individual with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769764	SCV000901186	uncertain significance	Cardiomyopathy	2021-12-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001101122	SCV001257695	uncertain significance	Dilated cardiomyopathy 1AA	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Fulgent Genetics, Fulgent Genetics	RCV002482983	SCV002783972	uncertain significance	Dilated cardiomyopathy 1AA; Myopathy, congenital, with structured cores and z-line abnormalities; Myopathy, distal, 6, adult-onset, autosomal dominant	2021-08-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766340	SCV003916568	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000766340	SCV004224822	uncertain significance	not provided	2022-04-08	criteria provided, single submitter	clinical testing	BP4
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