Submissions for variant NM_053025.4(MYLK):c.3242A>G (p.His1081Arg)

gnomAD frequency: 0.00235  dbSNP: rs113491038

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002311219	SCV000320581	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-01-23	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464822	SCV000560689	benign	Aortic aneurysm, familial thoracic 7	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000609787	SCV000714076	benign	not specified	2018-02-26	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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680571	SCV000807986	likely benign	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000609787	SCV001361519	benign	not specified	2019-08-19	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.3242A>G (p.His1081Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 251462 control chromosomes. The observed variant frequency is approximately 21 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 benign. To our knowledge, no occurrence of c.3242A>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported at our laboratory (FBN1 c.349C>T, p.Q117*), providing supporting evidence for a benign role. Four 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 (n=2)/likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
Fulgent Genetics, Fulgent Genetics	RCV002494796	SCV002795043	likely benign	Aortic aneurysm, familial thoracic 7; Megacystis-microcolon-intestinal hypoperistalsis syndrome 1	2021-09-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003930030	SCV004743288	benign	MYLK-related disorder	2019-05-31	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Breakthrough Genomics, Breakthrough Genomics	RCV001701984	SCV005264733	likely benign	not provided		criteria provided, single submitter	not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000609787	SCV001808736	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701984	SCV001929029	likely benign	not provided		no assertion criteria provided	clinical testing