Submissions for variant NM_053025.4(MYLK):c.3448+15G>A

gnomAD frequency: 0.00050  dbSNP: rs199789942

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219991	SCV000269300	benign	not specified	2015-09-16	criteria provided, single submitter	clinical testing	c.3448+15G>A in intron 18 of MYLK: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence. It has been identified in 1.1% (181/16508) of South Asian chromosomes in cluding 4 homozygous individuals by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org/; dbSNP rs199789942).
Illumina Laboratory Services, Illumina	RCV000284724	SCV000440298	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000219991	SCV000717483	benign	not specified	2017-07-10	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000219991	SCV001623310	benign	not specified	2021-04-20	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.3448+15G>A 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. 4/4 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 0.0016 in 250494 control chromosomes, predominantly at a frequency of 0.011 within the South Asian subpopulation in the gnomAD database, including 8 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 200-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Thoracic Aortic Aneurysms and Dissections phenotype (5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.3448+15G>A in individuals affected with Thoracic Aortic Aneurysms and Dissections and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as benign (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812226	SCV002049537	benign	not provided	2022-03-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002054377	SCV002321925	benign	Aortic aneurysm, familial thoracic 7	2025-01-22	criteria provided, single submitter	clinical testing