Submissions for variant NM_002471.4(MYH6):c.4666G>A (p.Glu1556Lys)

gnomAD frequency: 0.00007  dbSNP: rs148582147

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000647064	SCV000768851	uncertain significance	Hypertrophic cardiomyopathy 14	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1556 of the MYH6 protein (p.Glu1556Lys). This variant is present in population databases (rs148582147, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. 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: 537962). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH6 protein function with a positive 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001029736	SCV001192523	uncertain significance	Atrial septal defect 3	2018-10-11	criteria provided, single submitter	research	ACMG codes: PP3, PP4
Ambry Genetics	RCV002334166	SCV002636173	uncertain significance	Cardiovascular phenotype	2023-10-13	criteria provided, single submitter	clinical testing	The p.E1556K variant (also known as c.4666G>A), located in coding exon 31 of the MYH6 gene, results from a G to A substitution at nucleotide position 4666. The glutamic acid at codon 1556 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV005231226	SCV005879357	uncertain significance	not provided	2024-08-12	criteria provided, single submitter	clinical testing	The MYH6 c.4666G>A; p.Glu1556Lys variant (rs148582147), to our knowledge, is not reported in the medical literature in MYH6-related disorders but is reported in ClinVar (Variation ID: 537962). This variant is found in the general population with an overall allele frequency of 0.009% (24/280,660 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.807). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240383	SCV005884997	likely benign	not specified	2024-12-20	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.4666G>A (p.Glu1556Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 249316 control chromosomes. The observed variant frequency is approximately 3.4 - fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05). c.4666G>A has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with atrial septal defect (example: Bowling_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34930662). ClinVar contains an entry for this variant (Variation ID: 537962). Based on the evidence outlined above, the variant was classified as likely benign.