ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.4162C>T (p.Pro1388Ser) (rs61737942)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200105 SCV000249829 uncertain significance not provided 2015-06-01 criteria provided, single submitter clinical testing p.Pro1388Ser (P1388S) (CCT>TCT): c.4162 C>T in exon 53 of the COL5A1 gene (NM_000093.3) The P1388S variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge. The P1388S variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The P1388S 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. This substitution occurs at a position that is conserved across species. A missense mutation in nearby residue (G1393D) has been reported in association with EDS. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, the P1388S 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 missense mutations occur (Symoens et al., 2012). At this time we cannot definitively determine if Pro1388Ser is a disease-causing mutation or a rare benign variant. This variant was found in TAADV2-PANCARD
Ambry Genetics RCV000617226 SCV000738644 uncertain significance Cardiovascular phenotype 2016-11-08 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000634582 SCV000755912 uncertain significance Ehlers-Danlos syndrome, classic type 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1388 of the COL5A1 protein (p.Pro1388Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs61737942, ExAC 0.03%). This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 212972). 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.

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