ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.2963C>T (p.Thr988Met) (rs369072636)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199854 SCV000249975 uncertain significance not specified 2017-06-28 criteria provided, single submitter clinical testing p.Thr988Met (T988M) ACG>ATG: c.2963 C>T in exon 43 of the COL5A2 gene (NM_000393.3). The T988M variant in the COL5A2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The T988M variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The T988 residue is conserved in mammals. In silico analysis predicts T988M is damaging to the protein structure/function. The T988M 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 in nearby residues have been reported in association with Ehlers-Danlos syndrome or a related disorder, suggesting this region of the protein may be tolerant to change. With the clinical and molecular information available at this time, we cannot definitively determine if T988M is a disease-causing mutation or a rare benign variant. This variant was found in COL5A2, TAAD.
Invitae RCV000228925 SCV000284813 uncertain significance Ehlers-Danlos syndrome, classic type 2019-08-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 988 of the COL5A2 protein (p.Thr988Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs369072636, ExAC 0.04%). This variant has not been reported in the literature in individuals with COL5A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213112). 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 and their clinical significance is uncertain. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000199854 SCV000603203 uncertain significance not specified 2016-10-09 criteria provided, single submitter clinical testing

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