Submissions for variant NM_000257.4(MYH7):c.3977A>G (p.Lys1326Arg)

gnomAD frequency: 0.00001  dbSNP: rs730880786

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000168898	SCV000208559	uncertain significance	not provided	2013-05-30	criteria provided, single submitter	clinical testing	p.Lys1326Arg (AAG>AGG): c.3977 A>G in exon 30 of the MYH7 gene (NM_000257.2). The Lys1326Arg variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Lys1326Arg results in a conservative amino acid substitution of one positively charged amino acid with another at a position that is conserved across species. In silico analysis predicts Lys1326Arg is probably damaging to the protein structure/function. Mutations in nearby residues (Asn1327Lys, Ala1332Thr) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. However, data from control individuals were not available to assess whether Lys1326Arg may be a common benign variant in the general population. With the clinical and molecular information available at this time, we cannot definitively determine if Lys1326Arg is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s).
Invitae	RCV000459054	SCV000546184	uncertain significance	Hypertrophic cardiomyopathy	2022-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1326 of the MYH7 protein (p.Lys1326Arg). This variant is present in population databases (rs730880786, gnomAD 0.002%). This missense change has been observed in individual(s) with an inherited arrhythmia syndrome (PMID: 26743238). ClinVar contains an entry for this variant (Variation ID: 181237). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV001190442	SCV001357935	uncertain significance	Cardiomyopathy	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 1326 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with an inherited arrhythmia syndrome (PMID: 26743238). This variant has been identified in 3/246668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002372034	SCV002625103	uncertain significance	Cardiovascular phenotype	2021-03-22	criteria provided, single submitter	clinical testing	The p.K1326R variant (also known as c.3977A>G), located in coding exon 28 of the MYH7 gene, results from an A to G substitution at nucleotide position 3977. The lysine at codon 1326 is replaced by arginine, an amino acid with highly similar properties. This variant has been detected in a cohort of patients with arrhythmias and cardiomyopathies; however, details were limited (Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440). This amino acid position is highly 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.
Revvity Omics, Revvity	RCV000168898	SCV003817669	uncertain significance	not provided	2020-11-01	criteria provided, single submitter	clinical testing