Submissions for variant NM_002471.4(MYH6):c.5519A>G (p.Lys1840Arg)

gnomAD frequency: 0.00011  dbSNP: rs373629059

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000254495	SCV000319976	uncertain significance	Cardiovascular phenotype	2023-12-11	criteria provided, single submitter	clinical testing	The p.K1840R variant (also known as c.5519A>G), located in coding exon 34 of the MYH6 gene, results from an A to G substitution at nucleotide position 5519. The lysine at codon 1840 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy cohorts, in a dilated cardiomyopathy cohort, and in a hypoplastic left heart syndrome cohort; however, clinical details were limited (Rubattu S et al. Int J Mol Sci. 2016;17; Tomita-Mitchell A et al. Physiol. Genomics. 2016;48:912-921; Mazzarotto F et al. Genet Med, 2019 02;21:284-292; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477541	SCV000546143	uncertain significance	Hypertrophic cardiomyopathy 14	2025-01-17	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 1840 of the MYH6 protein (p.Lys1840Arg). This variant is present in population databases (rs373629059, gnomAD 0.01%). This missense change has been observed in individual(s) with MYH6-related conditions (PMID: 27483260, 27789736, 30847666, 32880476). ClinVar contains an entry for this variant (Variation ID: 264214). 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 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	RCV000521903	SCV000618330	uncertain significance	not provided	2020-01-23	criteria provided, single submitter	clinical testing	Reported in one individual with late-onset hypertrophic cardiomyopathy and one individual with hypoplastic left heart syndrome (Rubattu et al., 2016; Tomita-Mitchell et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 264214; Landrum et al., 2016); At the protein level, in silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; At the mRNA level, in-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 27483260, 27789736, 30847666, 32880476)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256805	SCV001433260	uncertain significance	Left ventricular noncompaction 1	2019-01-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262777	SCV001440769	uncertain significance	Dilated cardiomyopathy 1EE	2019-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469091	SCV002766190	uncertain significance	not specified	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.5519A>G (p.Lys1840Arg) results in a conservative amino acid change located in the Myosin tail (IPR002928) of 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 5.6e-05 in 250862 control chromosomes. The observed variant frequency is approximately 2.23 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. c.5519A>G has been reported in the literature in individuals affected with Cardiomyopathy and Hypoplastic left heart syndrome without evidence of causality (e.g. Tomita-Mitchell_2016, Rubattu_2016, Preveden_2022). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002479985	SCV002777294	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-08-30	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000521903	SCV001742433	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000521903	SCV001921230	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000521903	SCV001959198	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000521903	SCV001966847	uncertain significance	not provided		no assertion criteria provided	clinical testing