ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.399G>T (p.Gln133His) (rs140148380)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617037 SCV000319429 likely benign Cardiovascular phenotype 2019-02-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Illumina Clinical Services Laboratory,Illumina RCV001000031 SCV000440346 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 RCV000427577 SCV000536063 likely benign not specified 2017-07-24 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.
Invitae RCV001000031 SCV000560694 benign Aortic aneurysm, familial thoracic 7 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000031 SCV000604385 benign Aortic aneurysm, familial thoracic 7 2018-12-23 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000590924 SCV000700124 likely benign Familial thoracic aortic aneurysm 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. No known history of familial thoracic aortic aneurysm. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000427577 SCV000701929 likely benign not specified 2016-11-03 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000427577 SCV000740627 likely benign not specified 2017-06-13 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170677 SCV001333271 benign Familial thoracic aortic aneurysm and aortic dissection 2017-12-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000427577 SCV001338667 likely benign not specified 2020-04-27 criteria provided, single submitter clinical testing Variant summary: MYLK c.399G>T (p.Gln133His) 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 0.0018 in 251440 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 725 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-06), strongly suggesting that the variant is benign. c.399G>T has been reported in the literature (Milewicz_2017). This report however, does not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=7) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

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