Submissions for variant NM_001103.4(ACTN2):c.556C>T (p.Leu186Phe)

gnomAD frequency: 0.00003  dbSNP: rs371930065

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229218	SCV000285875	uncertain significance	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 186 of the ACTN2 protein (p.Leu186Phe). This variant is present in population databases (rs371930065, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 238302). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
GeneDx	RCV000487140	SCV000567802	uncertain significance	not provided	2023-07-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257)
Ambry Genetics	RCV000620752	SCV000740154	uncertain significance	Cardiovascular phenotype	2023-06-20	criteria provided, single submitter	clinical testing	The p.L186F variant (also known as c.556C>T), located in coding exon 6 of the ACTN2 gene, results from a C to T substitution at nucleotide position 556. The leucine at codon 186 is replaced by phenylalanine, an amino acid with highly similar properties. In a study of cardiomyopathy clinical genetic testing, this alteration was reported in one individual; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This variant was also detected in a sudden unexplained death cohort (Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:[Epub ahead of print]). This amino acid position is well conserved in available vertebrate species; however, phenylalanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769751	SCV000901173	uncertain significance	Cardiomyopathy	2020-11-02	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852593	SCV000995295	likely benign	Long QT syndrome	2017-10-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001098951	SCV001255353	uncertain significance	Dilated cardiomyopathy 1AA	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Revvity Omics, Revvity	RCV000487140	SCV003822561	uncertain significance	not provided	2021-12-08	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000487140	SCV000925025	uncertain significance	not provided	2016-03-01	no assertion criteria provided	provider interpretation