Submissions for variant NM_002471.4(MYH6):c.2591C>T (p.Thr864Met)

gnomAD frequency: 0.00008  dbSNP: rs200153625

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172564	SCV000050991	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Blueprint Genetics	RCV000208173	SCV000264069	uncertain significance	Primary familial hypertrophic cardiomyopathy	2015-03-26	criteria provided, single submitter	clinical testing
Invitae	RCV000821750	SCV000962519	uncertain significance	Hypertrophic cardiomyopathy 14	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 864 of the MYH6 protein (p.Thr864Met). This variant is present in population databases (rs200153625, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 192122). 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.
GeneDx	RCV000172564	SCV002526487	uncertain significance	not provided	2022-06-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23861362)
Ambry Genetics	RCV002433759	SCV002745411	uncertain significance	Cardiovascular phenotype	2022-11-15	criteria provided, single submitter	clinical testing	The p.T864M variant (also known as c.2591C>T), located in coding exon 19 of the MYH6 gene, results from a C to T substitution at nucleotide position 2591. The threonine at codon 864 is replaced by methionine, an amino acid with similar properties. This variant has been detected in a case with hypoplastic left heart syndrome (Theis JL et al. Circ Genom Precis Med. 2021 02;14(1):e003126). This variant has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is poorly 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.
Dept of Medical Biology, Uskudar University	RCV003318361	SCV004021989	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: Not met
CeGaT Center for Human Genetics Tuebingen	RCV000172564	SCV005093361	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MYH6: BP4, BS2