ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.1292A>G (p.Lys431Arg) (rs144602736)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000757127 SCV000249955 uncertain significance not provided 2018-11-29 criteria provided, single submitter clinical testing TAAD is a genetically heterogeneous disorder characterized by aortic dilatation, aneurysms, dissections and/or aneurysms of other major arteries. c.1292 A>G in exon 20 of the COL5A2 gene (NM_000393.3). Approximately 4% of patients with autosomal dominant Ehlers-Danlos syndrome, classic type, have been reported to have a mutation in the COL5A2 gene (Malfait F et al., 2011).The K431R variant in the COL5A2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. K431R results in a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The K431 residue is conserved through fish. The K431R variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, no mutations affecting nearby residues have been reported indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD.
Illumina Clinical Services Laboratory,Illumina RCV000397178 SCV000425653 uncertain significance Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000476732 SCV000547875 uncertain significance Ehlers-Danlos syndrome, classic type 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 431 of the COL5A2 protein (p.Lys431Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213094). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function and mRNA splicing. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757127 SCV000885249 uncertain significance not provided 2018-02-16 criteria provided, single submitter clinical testing The COL5A2 c.1292A>G; p.Lys431Arg variant (rs144602736), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.006% (identified on 14 out of 245,942 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 213094). The lysine at position 431 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Lys431Arg variant on protein structure and function provide conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging ). Based on the available information, the clinical significance of the p.Lys431Arg variant cannot be determined with certainty.

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