Submissions for variant NM_001103.4(ACTN2):c.2423C>T (p.Thr808Ile)

dbSNP: rs148833906

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459293	SCV000553764	likely benign	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2024-01-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000523122	SCV000621256	uncertain significance	not provided	2021-09-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#412276; Landrum et al., 2016)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290571	SCV001478647	uncertain significance	not specified	2021-01-28	criteria provided, single submitter	clinical testing	Variant summary: ACTN2 c.2423C>T (p.Thr808Ile) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251494 control chromosomes, predominantly at a frequency of 0.00055 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2423C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002446846	SCV002735189	uncertain significance	Cardiovascular phenotype	2022-07-18	criteria provided, single submitter	clinical testing	The p.T808I variant (also known as c.2423C>T), located in coding exon 20 of the ACTN2 gene, results from a C to T substitution at nucleotide position 2423. The threonine at codon 808 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not 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.
Fulgent Genetics, Fulgent Genetics	RCV002506133	SCV002816230	uncertain significance	Dilated cardiomyopathy 1AA; Myopathy, congenital, with structured cores and z-line abnormalities; Myopathy, distal, 6, adult-onset, autosomal dominant	2021-09-13	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678698	SCV000804860	uncertain significance	Primary dilated cardiomyopathy	2016-11-30	no assertion criteria provided	clinical testing