Submissions for variant NM_002471.3(MYH6):c.5642A>G (p.Lys1881Arg) (rs750886219)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Integrated Genetics/Laboratory Corporation of America	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.
Invitae	RCV000796615	SCV000936135	uncertain significance	Familial hypertrophic cardiomyopathy 14	2018-07-20	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with arginine at codon 1881 of the MYH6 protein (p.Lys1881Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs750886219, ExAC 0.05%). This variant has not been reported in the literature in individuals with MYH6-related disease. ClinVar contains an entry for this variant (Variation ID: 496160). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	Dilated cardiomyopathy	2019-05-08	criteria provided, single submitter	clinical testing

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