ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.4121C>T (p.Thr1374Met) (rs151115748)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000762590 SCV000567471 uncertain significance not provided 2018-05-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL5A1 gene. The T1374M 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 T1374M 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 only conserved through mammals and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, the T1374M 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).
Invitae RCV000552288 SCV000631514 uncertain significance Ehlers-Danlos syndrome, classic type 2019-11-07 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1374 of the COL5A1 protein (p.Thr1374Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs151115748, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 419573). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; 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.
Ambry Genetics RCV000618739 SCV000738619 uncertain significance Cardiovascular phenotype 2016-11-07 criteria provided, single submitter clinical testing Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000762590 SCV000892923 uncertain significance not provided 2019-08-01 criteria provided, single submitter clinical testing

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