Submissions for variant NM_053025.4(MYLK):c.1007C>T (p.Pro336Leu)

gnomAD frequency: 0.00106  dbSNP: rs35912339

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173911	SCV000225087	benign	not specified	2015-05-21	criteria provided, single submitter	clinical testing
Invitae	RCV001082109	SCV000291185	benign	Aortic aneurysm, familial thoracic 7	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000769342	SCV000319547	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-03-22	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.
GeneDx	RCV000757536	SCV000530487	likely benign	not provided	2022-05-23	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680576	SCV000807991	likely benign	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757536	SCV000885796	likely benign	not provided	2023-10-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769342	SCV000900725	benign	Familial thoracic aortic aneurysm and aortic dissection	2023-04-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001082109	SCV001311719	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	RCV000173911	SCV001338137	benign	not specified	2020-02-03	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.1007C>T (p.Pro336Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 248810 control chromosomes, including 1 homozygote (gnomAD). The variant was predominantly observed within the South Asian subpopulation (at a frequency of 0.0039), and the European (non-Finnish) subpopulation (at a frequency of 0.0021) in the gnomAD database. These frequencies are approximately 150-fold and 85-fold higher (respectively) than 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.1007C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (2x) / likely benign (5x). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000757536	SCV004155431	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MYLK: BP4, BS2
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000757536	SCV001798323	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000757536	SCV001809244	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000757536	SCV001931389	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000757536	SCV001966019	likely benign	not provided		no assertion criteria provided	clinical testing