ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.4175G>A (p.Arg1392Lys) (rs863223479)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197819 SCV000249911 uncertain significance not provided 2018-04-10 criteria provided, single submitter clinical testing p.Arg1392Lys (AGG>AAG): c.4175 G>A in exon 53 of the COL5A1 gene (NM_000093.3) The R1392K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R1392K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. Additionally, a missense mutation (G1393D) in a nearby residue has been reported in association with EDS, supporting the functional significance of this region of the protein. However, the R1392K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD
Ambry Genetics RCV000620605 SCV000738626 uncertain significance Cardiovascular phenotype 2016-07-22 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000634588 SCV000755918 uncertain significance Ehlers-Danlos syndrome, classic type 2018-07-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 1392 of the COL5A1 protein (p.Arg1392Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 213052). 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.

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