Submissions for variant NM_002471.4(MYH6):c.1014C>A (p.Asp338Glu)

dbSNP: rs763533477

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neuberg Centre For Genomic Medicine, NCGM	RCV001507087	SCV001712061	uncertain significance	Hypertrophic cardiomyopathy 14		criteria provided, single submitter	clinical testing	The missense variant p.D338E in MYH6 (NM_002471.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The missense variant c.1014C>A (p.D338E) in MYH6 (NM_002471.3) is observed in 1/30616 (0.0033%) alleles from individuals of South Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. There is a small physicochemical difference between aspartic acid and glutamic acid, which is not likely to impact secondary protein structure as these residues share similar properties. For these reasons, this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001507087	SCV003518093	uncertain significance	Hypertrophic cardiomyopathy 14	2022-08-27	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 338 of the MYH6 protein (p.Asp338Glu). This variant is present in population databases (rs763533477, 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: 1162258).