ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.4289-4C>G (rs376670657)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000214485 SCV000269307 benign not specified 2013-04-04 criteria provided, single submitter clinical testing 4289-4C>G in intron 24 of MYLK: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 0.6% (27/4406) of African American chromosomes fr om a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu/EVS).
Invitae RCV000234085 SCV000291200 benign Aortic aneurysm, familial thoracic 7 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000214485 SCV000535618 likely benign not specified 2017-09-27 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000214485 SCV000705111 benign not specified 2017-02-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620551 SCV000738361 likely benign Cardiovascular phenotype 2018-09-11 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Illumina Clinical Services Laboratory,Illumina RCV000234085 SCV001309792 likely benign 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 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.
Integrated Genetics/Laboratory Corporation of America RCV000214485 SCV001362532 benign not specified 2019-12-16 criteria provided, single submitter clinical testing Variant summary: MYLK c.4289-4C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00095 in 250734 control chromosomes, predominantly at a frequency of 0.0062 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 248 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 African or African-American origin. To our knowledge, no occurrence of c.4289-4C>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions (evaluation after 2014) cite the variant twice as benign and twice as likely benign. Based on the evidence outlined above, the variant was classified as benign.

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