Submissions for variant NM_053025.4(MYLK):c.755-12C>T

gnomAD frequency: 0.00212  dbSNP: rs138877679

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000441344	SCV000532220	benign	not specified	2017-12-20	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000441344	SCV000711379	likely benign	not specified	2013-04-04	criteria provided, single submitter	clinical testing	c.755-12C>T in intron 8 of MYLK: This variant is not expected to have clinical significance because it does not cause the splice site sequence to diverge from consensus and it has been identified in 0.2% (183/121404) chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1388776 79).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659936	SCV000781840	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001146464	SCV001307210	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000441344	SCV001362531	benign	not specified	2019-12-16	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.755-12C>T 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 0.002 in 251476 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 79-folds over the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.755-12C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions (evaluation after 2014) cite the variant once as likely benign and once as benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810939	SCV002049287	likely benign	not provided	2023-09-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001146464	SCV002367400	benign	Aortic aneurysm, familial thoracic 7	2024-01-31	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001810939	SCV005264749	likely benign	not provided		criteria provided, single submitter	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000441344	SCV001932404	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000441344	SCV001975291	benign	not specified		no assertion criteria provided	clinical testing