Submissions for variant NM_002471.4(MYH6):c.1007C>G (p.Ala336Gly)

dbSNP: rs138572790

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477183	SCV000546166	uncertain significance	Hypertrophic cardiomyopathy 14	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 336 of the MYH6 protein (p.Ala336Gly). This variant is present in population databases (rs138572790, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 312879). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV000620439	SCV000735539	uncertain significance	Cardiovascular phenotype	2023-11-08	criteria provided, single submitter	clinical testing	The p.A336G variant (also known as c.1007C>G), located in coding exon 10 of the MYH6 gene, results from a C to G substitution at nucleotide position 1007. The alanine at codon 336 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in cardiac genetic testing cohorts; however, clinical details were limited, and additional cardiac-related alterations were detected in some cases (Haas J et al. Eur Heart J, 2015 May;36:1123-35a; Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769428	SCV000900821	uncertain significance	Cardiomyopathy	2017-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001529961	SCV002559720	uncertain significance	not provided	2024-03-12	criteria provided, single submitter	clinical testing	Identified in patients with cardiomyopathy in the published literature (PMID: 25163546, 28771489); at least one patient harbored an additional cardiogenetic variant; 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: 28771489, Yalntepe2020[CaseReport], 25163546, 30847666)
MGZ Medical Genetics Center	RCV002288969	SCV002579475	uncertain significance	Dilated cardiomyopathy 1EE	2021-08-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504080	SCV002814477	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-08-12	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529961	SCV001744351	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529961	SCV001918971	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001529961	SCV001933022	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529961	SCV001953930	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529961	SCV001973196	uncertain significance	not provided		no assertion criteria provided	clinical testing