Submissions for variant NM_001103.4(ACTN2):c.1040C>T (p.Thr347Met)

gnomAD frequency: 0.00013  dbSNP: rs727504590

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171859	SCV000050878	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155763	SCV000205474	uncertain significance	not specified	2013-07-18	criteria provided, single submitter	clinical testing	The Thr347Met variant in ACTN2 has not been reported in individuals with cardiom yopathy or in large population studies. Computational analyses (biochemical amin o acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that th e Thr347Met variant may impact the protein, though this information is not predi ctive enough to determine pathogenicity. Additional information is needed to ful ly assess the clinical significance of this variant.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415429	SCV000492709	uncertain significance	Syncope; Hypertrophic cardiomyopathy	2015-10-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079030	SCV000760183	likely benign	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2024-12-18	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852594	SCV000995296	likely benign	Cardiomyopathy	2019-01-31	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198290	SCV001369171	uncertain significance	Dilated cardiomyopathy 1AA	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155763	SCV001448531	likely benign	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: ACTN2 c.1040C>T (p.Thr347Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251460 control chromosomes, predominantly at a frequency of 0.00098 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 39-fold the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1040C>T has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Nunn_2016, Cuenca_2016). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other ClinVar submitters (evaluation after 2014) reported the variant with conflicting assessments (likely benign, n=2; uncertain significance, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000171859	SCV001715417	uncertain significance	not provided	2019-07-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000171859	SCV001796039	uncertain significance	not provided	2020-06-03	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance or as a likely benign variant by other clinical laboratories (ClinVar Variant ID# 178985; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26899768)
Ambry Genetics	RCV002390359	SCV002700537	likely benign	Cardiovascular phenotype	2019-11-12	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.
Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	RCV004765316	SCV005374723	uncertain significance	Hypertrophic cardiomyopathy		no assertion criteria provided	research