ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.34C>T (p.Leu12Phe) (rs768807471)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196741 SCV000250002 uncertain significance not provided 2017-12-14 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. 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).p.Leu12Phe (L12F) CTC>TTC: c.34 C>T in exon 1 of the COL5A2 gene (NM_000393.3)A variant of unknown significance has been identified in the COL5A2 gene. The L12F variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The L12F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is mostly conserved in mammals; however, F is present as the wild type in several species from Wallaby and beyond. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. No missense mutations in nearby residues have been reported in association with COL5A2-related disorder suggesting this region of the protein may be tolerant of change. Furthermore, the L12F variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of missense mutations occur (Symoens et al., 2012). However, the L12F variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variantThis variant was found in TAADV2-1.
Invitae RCV000553325 SCV000631597 uncertain significance Ehlers-Danlos syndrome, classic type 2017-06-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 12 of the COL5A2 protein (p.Leu12Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs768807471, ExAC 0.002%). This variant has not been reported in the literature in individuals with a COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213139). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on COL5A2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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