Submissions for variant NM_053025.4(MYLK):c.382G>A (p.Ala128Thr)

gnomAD frequency: 0.00007  dbSNP: rs147840022

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002311139	SCV000320221	benign	Familial thoracic aortic aneurysm and aortic dissection	2016-12-08	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.
Invitae	RCV000456207	SCV000560665	benign	Aortic aneurysm, familial thoracic 7	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000613694	SCV000715930	benign	not specified	2017-06-08	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.
Illumina Laboratory Services, Illumina	RCV000456207	SCV001310181	likely benign	Aortic aneurysm, familial thoracic 7	2018-03-06	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	RCV000613694	SCV001442704	likely benign	not specified	2020-10-19	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.382G>A (p.Ala128Thr) results in a non-conservative amino acid change in 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 0.0013 in 251426 control chromosomes, predominantly at a frequency of 0.01 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 200 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Thoracic Aortic Aneurysms and Dissections phenotype (5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.382G>A in individuals affected with Thoracic Aortic Aneurysms and Dissections and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001572878	SCV003799847	likely benign	not provided	2022-03-31	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001572878	SCV001797929	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001572878	SCV001809071	likely benign	not provided		no assertion criteria provided	clinical testing