Submissions for variant NM_053025.4(MYLK):c.1991A>G (p.Gln664Arg)

gnomAD frequency: 0.00041  dbSNP: rs200273207

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214592	SCV000272079	uncertain significance	not specified	2015-04-09	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Gln664Arg var iant in MYLK has not been previously reported in individuals with connective tis sue disorder, but it has been identified in 0.15% (25/16508) of South Asian chro mosomes and 0.03% (23/66702) of European chromosomes by the Exome Aggregation Co nsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200273207). Computationa l prediction tools and conservation analysis do not provide strong support for o r against an impact to the protein. In summary, while the clinical significance of the p.Gln664Arg variant is uncertain, its frequency suggests that it is more likely to be benign.
Ambry Genetics	RCV000769336	SCV000320049	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-10-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082057	SCV000560698	likely benign	Aortic aneurysm, familial thoracic 7	2025-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001697219	SCV000576713	likely benign	not provided	2021-04-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25944730)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001697219	SCV000885797	likely benign	not provided	2023-03-29	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769336	SCV000900716	benign	Familial thoracic aortic aneurysm and aortic dissection	2021-06-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000214592	SCV001361248	likely benign	not specified	2022-06-06	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.1991A>G (p.Gln664Arg) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 251488 control chromosomes, predominantly at a frequency of 0.0017 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 680 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1991A>G has been reported in the literature in individuals affected with Aortopathy (Wooderchak-Donahue_2015). This report however, 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. Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=3) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003919882	SCV004734048	likely benign	MYLK-related disorder	2023-08-09	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).