ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.3614T>C (p.Val1205Ala) (rs148110552)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000272947 SCV000425622 uncertain significance Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000471046 SCV000547877 uncertain significance Ehlers-Danlos syndrome, classic type 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1205 of the COL5A2 protein (p.Val1205Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs148110552, ExAC 0.01%). This variant has not been reported in the literature in individuals with COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 333134). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD": "Class C0"). 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 RCV000478578 SCV000571664 uncertain significance not provided 2016-09-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL5A2 gene. The V1205A variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V1205A variantwas not observed with any significant frequency in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. Nevertheless, the V1205A variant is a conservative amino acid substitution, which is not likely toimpact secondary protein structure as these residues share similar properties. This substitution occurs at a positionthat is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not thevariant is damaging to the protein structure/function. Furthermore, the V1205A does not affect a Glycine residue in aGly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of pathogenic missense variantsoccur (Stenson et al., 2014; Symoens et al., 2012). However, in contrast to several other collagen genes, relativelyfew pathogenic Glycine substitutions have been reported in COL5A2 in association with Ehlers-Danlos syndrome.Most pathogenic variants in COL5A2 are in-frame splice site changes that cause exon skipping (Symoens et al.,2012).

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