ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.1968G>T (p.Trp656Cys) (rs138172035)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617864 SCV000738357 likely benign Cardiovascular phenotype 2020-07-08 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000680564 SCV000807978 likely benign Connective tissue disease 2018-06-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757532 SCV000885792 benign not provided 2017-09-12 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.
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.

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