Submissions for variant NM_002471.4(MYH6):c.4328C>A (p.Ala1443Asp)

gnomAD frequency: 0.00019  dbSNP: rs727503234

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151213	SCV000199051	uncertain significance	not specified	2013-11-01	criteria provided, single submitter	clinical testing	The Ala1443Asp variant in MYH6 has been reported in 1 individual with congenital heart disease (ASD) and was absent from at least 960 control chromosomes (Grana dos-Riveron 2010, Granados-Riveron 2012). It was also absent from large populati on studies. Computational analyses (biochemical amino acid properties, conservat ion, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the pr otein, though this information is not predictive enough to determine pathogenici ty. In summary, additional information is needed to fully assess the clinical si gnificance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701551	SCV000830355	uncertain significance	Hypertrophic cardiomyopathy 14	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1443 of the MYH6 protein (p.Ala1443Asp). This variant is present in population databases (rs727503234, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of MYH6-related conditions (PMID: 20656787, 24082139, 27789736, 28416588, 29875424, 31513939, 31737537, 32880476, 36890431). ClinVar contains an entry for this variant (Variation ID: 164221). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH6 protein function with a negative predictive value of 80%. 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.
Center for Human Genetics, University of Leuven	RCV000768516	SCV000886829	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000761595	SCV000891756	uncertain significance	Atrial septal defect 3	2018-07-12	criteria provided, single submitter	research	ACMG codes: PP3
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845518	SCV000987621	uncertain significance	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000761595	SCV002557449	uncertain significance	Atrial septal defect 3	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (26 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin tail domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported many times as a VUS within European cohorts (ClinVar, LOVD, cardiodb, PMID: 30847666, PMID: 29875424). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002326864	SCV002633263	uncertain significance	Cardiovascular phenotype	2022-07-07	criteria provided, single submitter	clinical testing	The p.A1443D variant (also known as c.4328C>A), located in coding exon 28 of the MYH6 gene, results from a C to A substitution at nucleotide position 4328. The alanine at codon 1443 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been reported in various cohorts, including those with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), congenital heart defects (including a hypoplastic left heart syndrome (HLHS) cohort), as well as in a cohort of volunteers who underwent exome sequencing; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Tomita-Mitchell A et al. Physiol. Genomics, 2016 12;48:912-921; Granados-Riveron JT et al. Congenit Heart Dis Oct;7:151-9; Gonzalez-Garay ML et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Oct;110:16957-62; Mazzarotto F et al. Genet. Med., 2019 02;21:284-292; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002478427	SCV002785153	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-09-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000995125	SCV003761926	uncertain significance	not provided	2023-01-25	criteria provided, single submitter	clinical testing	Identified in individuals with various forms of cardiac disease, including congenital heart defects, atrial fibrillation, and cardiomyopathies (Granados-Riveron et al., 2010; Granados-Riveron et al., 2012; Gonzalez-Garay et al., 2013; Tomita-Mitchell et al., 2016; Dal Ferro et al., 2017; Gigli et al., 2019; Marschall et al., 2019; Robyns et al., 2020; Verdonschot et al., 2020; Bowling et al., 2022; Zhu et al., 2022); 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: 28416588, 20656787, 27789736, 29875424, 31514951, 32880476, 35456442, 31513939, 31737537, 22011241, 34930662, 24082139)
Revvity Omics, Revvity	RCV000995125	SCV003809565	uncertain significance	not provided	2022-04-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151213	SCV004803997	uncertain significance	not specified	2024-01-30	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.4328C>A (p.Ala1443Asp) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of 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 8.4e-05 in 251422 control chromosomes (gnomAD). The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.4328C>A has been reported in the literature in individuals affected or suspected with Cardiomyopathy (examples: Gonzalez_2013, Dal ferro_2017, Gigli_2019, Mazzarotto_2019, Marschall_2019, Verdonschot_2020), Congenital heart defects (Granados-Riveron_2010), atrial septal defects (Bowling_2022) and Hypoplastic left heart syndrome (Tomita-Mitchell_2016, Najib_ 2023). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. The following publications have been ascertained in the context of this evaluation (PMID: 34930662, 28416588, 31514951, 24082139, 22011241, 31737537, 29875424, 36890431, 31513939, 27789736, 32880476, 35456442). ClinVar contains an entry for this variant (Variation ID: 164221). Based on the evidence outlined above, the variant was classified as uncertain significance.
Blueprint Genetics	RCV000157341	SCV000207078	uncertain significance	Primary dilated cardiomyopathy	2014-09-29	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000995125	SCV001740297	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000995125	SCV001918308	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000995125	SCV001952722	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000995125	SCV001980014	uncertain significance	not provided		no assertion criteria provided	clinical testing