ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.514G>T (p.Val172Phe) (rs150147262)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619401 SCV000738565 uncertain significance Cardiovascular phenotype 2017-06-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Blueprint Genetics RCV000157144 SCV000206867 uncertain significance Aortic valve disorder; Thoracic aortic aneurysm and aortic dissection 2014-04-08 no assertion criteria provided clinical testing
Center for Human Genetics, Inc RCV000659439 SCV000781253 likely benign Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000199784 SCV000249872 uncertain significance not provided 2018-12-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL5A1 gene. The V172F variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed both independently, and in conjunction with other variants, in multiple individuals referred for Marfan/TAAD genetic testing at GeneDx, although segregation data from these individuals is not sufficient to determine the pathogenicity of this variant. This substitution occurs at a position where only amino acids with similar properties to valine (V) are tolerated across species, and V172F is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, V172F does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A1gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). Furthermore, this variant has been observed in 39/65444 (0.06%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000554095 SCV000631540 uncertain significance Ehlers-Danlos syndrome, classic type 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 172 of the COL5A1 protein (p.Val172Phe). The valine residue is moderately conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs150147262, ExAC 0.06%), 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 a COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 180298). 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on COL5A1 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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