Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001356273 | SCV000604393 | uncertain significance | not provided | 2020-06-28 | criteria provided, single submitter | clinical testing | The p.Gly76Arg variant (rs368413008) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.01 percent (identified on 1 out of 13006 chromosomes) and is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.004 percent (identified on 5 out of 120192 chromosomes). The glycine at position 76 is weakly conserved (considering 12 species, Alamut v.2.9.0) but computational analyses of the effects of the p.Gly76Arg variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Gly76Arg variant with certainty. |
| Invitae | RCV000548227 | SCV000650523 | uncertain significance | Aortic aneurysm, familial thoracic 7 | 2023-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 76 of the MYLK protein (p.Gly76Arg). This variant is present in population databases (rs368413008, gnomAD 0.006%). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 439944). 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 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. |
| Ambry Genetics | RCV002314886 | SCV000739311 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2016-10-21 | criteria provided, single submitter | clinical testing | The p.G76R variant (also known as c.226G>A), located in coding exon 2 of the MYLK gene, results from a G to A substitution at nucleotide position 226. The glycine at codon 76 is replaced by arginine, an amino acid with dissimilar properties, and is located in the Ig-like C2-type 1 domain. This variant was previously reported in the SNPDatabase as rs368413008. Based on data from ExAC, the A allele has an overall frequency less than 0.01% (4/105288). Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied and 0.01% (1/8600) European American alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| CHEO Genetics Diagnostic Laboratory, |
RCV002314886 | SCV003838317 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2021-07-14 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001356273 | SCV001551395 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The MYLK p.Gly76Arg variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs368413008) and ClinVar (classified as uncertain significance by Invitae, ARUP laboratories and Ambry Genetics). The variant was identified in control databases in 10 of 251016 chromosomes at a frequency of 0.00003984 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 1 of 34574 chromosomes (freq: 0.000029), European (non-Finnish) in 8 of 113424 chromosomes (freq: 0.000071) and Other in 1 of 6118 chromosomes freq: 0.0001635) but was not observed in the South Asian, European (Finnish), or East Asian populations. The p.Gly76 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% chance of a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |