Submissions for variant NM_053025.4(MYLK):c.479C>G (p.Pro160Arg)

gnomAD frequency: 0.00440  dbSNP: rs111256888

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000253654	SCV000315307	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000769344	SCV000319371	benign	Familial thoracic aortic aneurysm and aortic dissection	2015-02-11	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
GeneDx	RCV000253654	SCV000533277	benign	not specified	2016-12-01	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.
Invitae	RCV001000299	SCV000560656	benign	Aortic aneurysm, familial thoracic 7	2024-01-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769344	SCV000900727	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2017-09-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812740	SCV001156975	benign	not provided	2021-04-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000253654	SCV001361520	benign	not specified	2019-10-15	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.479C>G (p.Pro160Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 250756 control chromosomes, predominantly at a frequency of 0.016 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 640 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.479C>G has been reported in the literature without strong evidence of causality (Pal_2017). This report does not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign (x3) and likely benign (x1). Based on the evidence outlined above, the variant was classified as benign.