Submissions for variant NM_002471.4(MYH6):c.934G>A (p.Ala312Thr)

gnomAD frequency: 0.00002  dbSNP: rs748143404

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000350031	SCV000385777	uncertain significance	Atrial septal defect	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000404777	SCV000385778	uncertain significance	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000296450	SCV000385779	uncertain significance	Hypertrophic cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690464	SCV000818150	uncertain significance	Hypertrophic cardiomyopathy 14	2024-06-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 312 of the MYH6 protein (p.Ala312Thr). This variant is present in population databases (rs748143404, gnomAD 0.008%). 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: 312880). 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	RCV001764281	SCV001998307	uncertain significance	not provided	2023-12-20	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics	RCV002446567	SCV002682323	uncertain significance	Cardiovascular phenotype	2023-12-08	criteria provided, single submitter	clinical testing	The p.A312T variant (also known as c.934G>A), located in coding exon 9 of the MYH6 gene, results from a G to A substitution at nucleotide position 934. The alanine at codon 312 is replaced by threonine, an amino acid with similar properties. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001764281	SCV004564231	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	The MYH6 c.934G>A; p.Ala312Thr variant (rs748143404), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 312880). This variant is found in the general population with an overall allele frequency of 0.002% (7/282,266 alleles) in the Genome Aggregation Database. The alanine at codon 312 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.292). Due to limited information, the clinical significance of the p.Ala312Thr variant is uncertain at this time.