Submissions for variant NM_053025.4(MYLK):c.169C>T (p.Arg57Trp)

gnomAD frequency: 0.00003  dbSNP: rs776636237

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000648734	SCV000770555	uncertain significance	Aortic aneurysm, familial thoracic 7	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 57 of the MYLK protein (p.Arg57Trp). This variant is present in population databases (rs776636237, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 539086). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYLK protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV002274080	SCV002559579	uncertain significance	not provided	2022-07-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002397280	SCV002714260	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-07-15	criteria provided, single submitter	clinical testing	The p.R57W variant (also known as c.169C>T), located in coding exon 2 of the MYLK gene, results from a C to T substitution at nucleotide position 169. The arginine at codon 57 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the Ig-like C2-type 1 domain. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483872	SCV002780859	uncertain significance	Aortic aneurysm, familial thoracic 7; Megacystis-microcolon-intestinal hypoperistalsis syndrome 1	2021-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155260	SCV003845064	uncertain significance	not specified	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.169C>T (p.Arg57Trp) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of 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 8.1e-06 in 246382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.169C>T in individuals affected with Thoracic Aortic Aneurysms And Dissections and no experimental evidence demonstrating its impact on protein function have been reported. 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003918057	SCV004735043	uncertain significance	MYLK-related disorder	2024-02-20	no assertion criteria provided	clinical testing	The MYLK c.169C>T variant is predicted to result in the amino acid substitution p.Arg57Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0082% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.