Submissions for variant NM_002471.4(MYH6):c.4036C>T (p.Arg1346Trp)

gnomAD frequency: 0.00007  dbSNP: rs372736126

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037495	SCV000061153	uncertain significance	not specified	2012-10-01	criteria provided, single submitter	clinical testing	The Arg1346Trp variant in MYH6 has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 1/8600 E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, and SIFT) suggest that this v ariant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of this variant.
Invitae	RCV000704961	SCV000833936	uncertain significance	Hypertrophic cardiomyopathy 14	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1346 of the MYH6 protein (p.Arg1346Trp). This variant is present in population databases (rs372736126, gnomAD 0.008%). This missense change has been observed in individual(s) with MYH6-related congenital heart defects (PMID: 35456442). ClinVar contains an entry for this variant (Variation ID: 44502). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037495	SCV001361608	uncertain significance	not specified	2019-10-30	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.4036C>T (p.Arg1346Trp) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250728 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4036C>T has been reported in the literature in an individual affected with Cardiomyopathy (Tariq_2012). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000995126	SCV001794855	uncertain significance	not provided	2022-09-20	criteria provided, single submitter	clinical testing	Identified in the apparently homozygous state in an individual with DCM referred for genetic testing at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in two unrelated individuals from cohorts of patients with congenital heart defects, but these individuals also harbored variants in other genes (Lu et al., 2022 and Zhu et al., 2022); This variant is associated with the following publications: (PMID: 34983622, 35456442)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798116	SCV002043191	uncertain significance	Cardiomyopathy	2019-10-29	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000704961	SCV004047889	uncertain significance	Hypertrophic cardiomyopathy 14		criteria provided, single submitter	clinical testing	The missense c.4036C>T(p.Arg1346Trp) variant in MYH6 gene has been submitted to ClinVar as a Variant of Uncertain Significance. It has not been reported in affected individuals. The variant is observed in 0.002% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Arg at position 1346 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance.