Submissions for variant NM_053025.4(MYLK):c.3987T>G (p.Asp1329Glu)

gnomAD frequency: 0.00558  dbSNP: rs9844788

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000247458	SCV000315294	benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV001087491	SCV000560691	benign	Aortic aneurysm, familial thoracic 7	2024-01-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812739	SCV000604375	benign	not provided	2023-09-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000247458	SCV000714918	benign	not specified	2017-01-23	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.
Ambry Genetics	RCV000770619	SCV000738422	benign	Familial thoracic aortic aneurysm and aortic dissection	2015-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770619	SCV000902070	benign	Familial thoracic aortic aneurysm and aortic dissection	2023-06-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001087491	SCV001309795	likely benign	Aortic aneurysm, familial thoracic 7	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000247458	SCV001361250	benign	not specified	2019-08-26	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.3987T>G (p.Asp1329Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0014 in 250338 control chromosomes, predominantly at a frequency of 0.02 within the African or African-American subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 800 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. Five ClinVar submitters (evaluation after 2014) cite the variant as benign (4x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.