Submissions for variant NM_001103.4(ACTN2):c.2147C>T (p.Thr716Met)

gnomAD frequency: 0.00024  dbSNP: rs193922635

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036896	SCV000060551	uncertain significance	not specified	2015-02-25	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Thr716Met var iant in ACTN2 has been previously identified by our laboratory in 4 individuals with a range of cardiac features (1 adult with HCM, 1 adult with ARVC, 1 adolesc ent with mitral valve prolapse, and 1 adult with LVH and a mildly dilated LA). I t has also been identified in 0.1% (39/66254) of European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1939226 35). Computational prediction tools and conservation analysis do not provide str ong support for or against an impact to the protein. In summary, while the clini cal significance of the p.Thr716Met variant is uncertain, these data suggest tha t it is more likely to be benign.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000172894	SCV000223885	uncertain significance	Hypertrophic cardiomyopathy 1	2015-03-20	criteria provided, single submitter	research	The ACTN2 Thr716Met variant has been previously reported to occur in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.0003, and sub-population frequency of European (non-Finnish) individuals at 0.00059 (39/66254 alleles). The variant is absent in the 1000 genomes project (http://www.1000genomes.org/). Threonine (Thr) at position 716 is relatively conserved across distantly related species, and in silico tools are supportive of a damaging effect (SIFT "deleterious"; PolyPhen2 "probably damaging"; MutationTaster "disease-causing"; CADD score = 19), however this alone cannot be considered as strong evidence for pathogenicity. We have identified the ACTN2 Thr716Met variant in a single HCM proband of European descent. The patient was diagnosed aged 50 years, with asymmetric septal hypertophy of 20mm, and no established family history of disease. Based on the limited evidence, we call this variant one of "uncertain significance".
GeneDx	RCV000766343	SCV000235697	likely benign	not provided	2021-02-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25333069, 25611685)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081956	SCV000285866	benign	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000251944	SCV000320657	likely benign	Cardiovascular phenotype	2018-09-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000624427	SCV000740540	uncertain significance	Primary familial hypertrophic cardiomyopathy	2017-04-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000029298	SCV000901191	benign	Cardiomyopathy	2018-07-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766343	SCV001147744	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	ACTN2: BS1
Illumina Laboratory Services, Illumina	RCV001101126	SCV001257699	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029298	SCV000051944	uncertain significance	Cardiomyopathy	2015-10-02	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000766343	SCV000925028	uncertain significance	not provided	2016-01-28	no assertion criteria provided	provider interpretation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766343	SCV001740133	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766343	SCV001927225	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766343	SCV001951988	likely benign	not provided		no assertion criteria provided	clinical testing