Submissions for variant NM_053025.4(MYLK):c.422+14G>C

gnomAD frequency: 0.00400  dbSNP: rs146112057

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000252705	SCV000315298	benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000252705	SCV000714098	benign	not specified	2017-01-30	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003656103	SCV001157831	benign	not provided	2023-10-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001000778	SCV001310180	likely benign	Aortic aneurysm, familial thoracic 7	2018-01-12	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	RCV000252705	SCV001362530	benign	not specified	2019-10-22	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.422+14G>C 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 0.001 in 251448 control chromosomes, predominantly at a frequency of 0.014 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 560 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.422+14G>C in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV001000778	SCV002401945	benign	Aortic aneurysm, familial thoracic 7	2024-01-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002479971	SCV002798842	likely benign	Aortic aneurysm, familial thoracic 7; Megacystis-microcolon-intestinal hypoperistalsis syndrome 1	2021-07-26	criteria provided, single submitter	clinical testing