Submissions for variant NM_002471.4(MYH6):c.5642A>G (p.Lys1881Arg)

gnomAD frequency: 0.00005  dbSNP: rs750886219

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586382	SCV000697930	likely benign	not provided	2016-09-29	criteria provided, single submitter	clinical testing	Variant summary: The MYH6 c.5642A>G (p.Lys1881Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 5/121356 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0004807 (5/10402). This frequency is about 19 times the estimated maximal expected allele frequency of a pathogenic MYH6 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796615	SCV000936135	uncertain significance	Hypertrophic cardiomyopathy 14	2024-11-13	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 1881 of the MYH6 protein (p.Lys1881Arg). This variant is present in population databases (rs750886219, gnomAD 0.03%). 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: 496160). 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) has been performed 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 MYH6 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852690	SCV000995399	likely benign	Primary dilated cardiomyopathy	2019-05-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002350414	SCV002651767	uncertain significance	Cardiovascular phenotype	2024-01-29	criteria provided, single submitter	clinical testing	The c.5642A>G (p.K1881R) alteration is located in exon 37 (coding exon 35) of the MYH6 gene. This alteration results from a A to G substitution at nucleotide position 5642, causing the lysine (K) at amino acid position 1881 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150290	SCV003838733	uncertain significance	Cardiomyopathy	2021-08-09	criteria provided, single submitter	clinical testing