Submissions for variant NM_053025.4(MYLK):c.5441C>T (p.Thr1814Ile)

gnomAD frequency: 0.00197  dbSNP: rs142220417

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000306545	SCV000440270	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000457820	SCV000560662	benign	Aortic aneurysm, familial thoracic 7	2024-01-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000306545	SCV000739265	benign	Familial thoracic aortic aneurysm and aortic dissection	2016-03-03	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269125	SCV001448376	benign	not specified	2020-11-30	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.5441C>T (p.Thr1814Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251246 control chromosomes, predominantly at a frequency of 0.006 within the African or African-American subpopulation in the gnomAD database (exomes dataset), including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 120 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 African or African-American origin. To our knowledge, no occurrence of c.5441C>T 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 without evidence for independent evaluation and classified the variant as VUS (1x), or benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001597109	SCV001831304	benign	not provided	2020-03-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003950198	SCV004764807	likely benign	MYLK-related condition	2023-05-23	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).