Submissions for variant NM_002471.4(MYH6):c.2575G>T (p.Gly859Trp)

dbSNP: rs369274077

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172030	SCV000054816	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Blueprint Genetics	RCV000208528	SCV000264068	uncertain significance	Heart disease	2015-07-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170243	SCV001332803	uncertain significance	Cardiomyopathy	2017-12-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001364234	SCV001560369	uncertain significance	Hypertrophic cardiomyopathy 14	2024-05-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 859 of the MYH6 protein (p.Gly859Trp). This variant is present in population databases (rs369274077, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 191718). 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.
Ambry Genetics	RCV002453597	SCV002739567	uncertain significance	Cardiovascular phenotype	2022-11-03	criteria provided, single submitter	clinical testing	The p.G859W variant (also known as c.2575G>T), located in coding exon 19 of the MYH6 gene, results from a G to T substitution at nucleotide position 2575. The glycine at codon 859 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been detected in individuals tested for hypertrophic and dilated cardiomyopathy and has co-occurred with a variant in the SOS1 gene in a sudden death case (van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309; Salfati EL et al. Genome Med. 2019 12;11(1):83). This alteration 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 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	RCV002492720	SCV002780606	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-09-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172030	SCV004042577	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	MYH6: PS4:Supporting, BP4
Clinical Genetics, Academic Medical Center	RCV000172030	SCV001918424	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172030	SCV001974007	uncertain significance	not provided		no assertion criteria provided	clinical testing