Submissions for variant NM_053025.4(MYLK):c.399G>T (p.Gln133His)

gnomAD frequency: 0.00167  dbSNP: rs140148380

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001170677	SCV000319429	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-02-16	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.
Illumina Laboratory Services, Illumina	RCV001000031	SCV000440346	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001579449	SCV000536063	likely benign	not provided	2021-05-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001000031	SCV000560694	benign	Aortic aneurysm, familial thoracic 7	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001579449	SCV000604385	benign	not provided	2021-09-01	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV001795472	SCV000700124	likely benign	Congenital aneurysm of ascending aorta	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of familial thoracic aortic aneurysm. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Eurofins Ntd Llc (ga)	RCV000427577	SCV000701929	likely benign	not specified	2016-11-03	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000427577	SCV000740627	likely benign	not specified	2017-06-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170677	SCV001333271	benign	Familial thoracic aortic aneurysm and aortic dissection	2017-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000427577	SCV001338667	likely benign	not specified	2020-04-27	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.399G>T (p.Gln133His) 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 0.0018 in 251440 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 725 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-06), strongly suggesting that the variant is benign. c.399G>T has been reported in the literature (Milewicz_2017). This report however, does not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=7) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001579449	SCV002011111	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001579449	SCV004011483	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MYLK: BP4, BS2
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579449	SCV001807279	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001579449	SCV001929757	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001579449	SCV001965879	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003909883	SCV004720666	likely benign	MYLK-related disorder	2019-05-29	no assertion criteria provided	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).