Submissions for variant NM_033118.4(MYLK2):c.549C>T (p.His183=)

gnomAD frequency: 0.00035  dbSNP: rs3746597

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039790	SCV000063479	benign	not specified	2012-06-01	criteria provided, single submitter	clinical testing	2.5% (18/734) Asian alleles from JBIC-allele - East Asian population in dbSNP
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463067	SCV000556766	benign	Hypertrophic cardiomyopathy 1	2025-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000039790	SCV000714704	benign	not specified	2018-02-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770574	SCV000902023	benign	Cardiomyopathy	2016-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000039790	SCV002651024	likely benign	not specified	2022-05-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039790	SCV003934060	benign	not specified	2023-05-17	criteria provided, single submitter	clinical testing	Variant summary: MYLK2 c.549C>T results in a synonymous change. The variant allele was found at a frequency of 0.0013 in 251068 control chromosomes, predominantly at a frequency of 0.017 within the East Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 700 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK2 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.549C>T in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV004716919	SCV005315010	benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV004745175	SCV005353466	likely benign	MYLK2-related disorder	2024-08-19	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).