Submissions for variant NM_053025.4(MYLK):c.1968G>T (p.Trp656Cys)

dbSNP: rs138172035

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000415658	SCV000440322	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.
GeneDx	RCV000757532	SCV000532158	likely benign	not provided	2021-09-27	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 31980526, 21055718)
Invitae	RCV000415658	SCV000560652	likely benign	Aortic aneurysm, familial thoracic 7	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000337416	SCV000738357	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-07-08	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	RCV000680564	SCV000807978	likely benign	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757532	SCV000885792	benign	not provided	2023-03-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000337416	SCV000900717	benign	Familial thoracic aortic aneurysm and aortic dissection	2019-04-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000420099	SCV001338138	likely benign	not specified	2020-02-03	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.1968G>T (p.Trp656Cys) results in a non-conservative amino acid change located in the fifth immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 251486 control chromosomes, predominantly at a frequency of 0.0021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 84 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 Non-Finnish European origin. c.1968G>T has been reported in the literature to be found in unaffected controls (Wang_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (1x) / likely benign (2x) or VUS (4x). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000757532	SCV004034019	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	MYLK: BP4
PreventionGenetics, part of Exact Sciences	RCV003950201	SCV004759100	likely benign	MYLK-related disorder	2023-09-13	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).
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415658	SCV000493775	uncertain significance	Aortic aneurysm, familial thoracic 7	2016-03-30	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000415658	SCV000607052	not provided	Aortic aneurysm, familial thoracic 7		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.