Submissions for variant NM_002471.4(MYH6):c.4097C>T (p.Ala1366Val)

gnomAD frequency: 0.00001  dbSNP: rs1085307922

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489332	SCV000577671	likely pathogenic	not provided	2015-07-24	criteria provided, single submitter	clinical testing	The A1366V variant in the MYH6 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The A1366V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common variant in these populations. The A1366V variant is a conservative amino acid substitution, which occurs in the coiled coil domain at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A different missense variant in the same residue (A1366D) has been reported in the Human Gene Mutation Database in association with congenital heart defects (Stenson et al., 2014), supporting the functional importance of this region of the protein. The A1366V variant is a strong candidate for a disease-causing variant. However, the possibility it may be a rare benign variant cannot be excluded
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989111	SCV004805766	uncertain significance	Atrial septal defect 3	2024-03-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004023262	SCV005018865	uncertain significance	Cardiovascular phenotype	2024-01-25	criteria provided, single submitter	clinical testing	The p.A1366V variant (also known as c.4097C>T), located in coding exon 27 of the MYH6 gene, results from a C to T substitution at nucleotide position 4097. The alanine at codon 1366 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005056067	SCV005717255	uncertain significance	Hypertrophic cardiomyopathy 14	2024-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1366 of the MYH6 protein (p.Ala1366Val). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 427048). 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.