ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.191C>T (p.Thr64Met) (rs777376620)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197223 SCV000249862 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL5A1 gene. The T64M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T64M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Finally, the T64M variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012).
Ambry Genetics RCV000617901 SCV000738673 uncertain significance Cardiovascular phenotype 2017-05-25 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001216070 SCV001387844 uncertain significance Ehlers-Danlos syndrome, classic type 2019-08-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 64 of the COL5A1 protein (p.Thr64Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs777376620, ExAC 0.01%). This variant has been observed in an individual affected with clinical features of Ehlers-Danlos syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 213005). 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 methionine 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, 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.

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