Submissions for variant NM_053025.4(MYLK):c.1609G>A (p.Val537Ile)

gnomAD frequency: 0.00026  dbSNP: rs199988497

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460571	SCV000550023	benign	Aortic aneurysm, familial thoracic 7	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001721500	SCV000572415	likely benign	not provided	2021-06-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001721500	SCV000604387	likely benign	not provided	2023-10-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313176	SCV000739261	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-06-08	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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659940	SCV000781844	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000460571	SCV001310061	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000482145	SCV001482186	benign	not specified	2021-02-22	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.1609G>A (p.Val537Ile) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 250926 control chromosomes. The observed variant frequency is approximately 8.6-fold 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 benign. To our knowledge, no occurrence of c.1609G>A in individuals affected with Thoracic Aortic Aneurysms And Dissections and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=1; likely benign, n=3; uncertain significance, n=2). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003942488	SCV004774755	likely benign	MYLK-related disorder	2021-01-11	criteria provided, single submitter	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).