ClinVar Genomic variation as it relates to human health

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.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1204 of the MYLK protein (p.Arg1204Trp). This variant is present in population databases (rs151294221, gnomAD 0.02%). This missense change has been observed in individual(s) with MYLK-related conditions (PMID: 28139901, 29907982; Invitae). ClinVar contains an entry for this variant (Variation ID: 342881). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYLK protein function with a negative predictive value of 80%. 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.

MYLK: BS2

Reported in a patient with a suspected heritable thoracic aortic disorder (Overwater et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29907982)

Variant summary: MYLK c.3610C>T (p.Arg1204Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 233298 control chromosomes. The observed variant frequency is approximately 2.83 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 benign. c.3610C>T has been reported in the literature in individuals affected with Thoracic Aortic Aneurysms And Dissections (D'Souza_2017, Overwater_2017), however these data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: six submitters classified the variant as VUS whle one classified as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

ACMG criteria used to clasify this variant: PP3SUP

The p.R1204W variant (also known as c.3610C>T), located in coding exon 17 of the MYLK gene, results from a C to T substitution at nucleotide position 3610. The arginine at codon 1204 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a thoracic aortic aneurysm and dissection (TAAD) cohort (Overwater E et al. Hum Mutat, 2018 09;39:1173-1192). This amino acid position is highly 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.