ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.263C>A (p.Pro88His) (rs149877855)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197910 SCV000249997 uncertain significance not provided 2018-08-20 criteria provided, single submitter clinical testing The P88H variant in the COL5A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P88H variant is observed in 39/276990 (0.014%) alleles in large population cohorts (Lek et al., 2016). The P88H 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P88H as a variant of uncertain significance
Illumina Clinical Services Laboratory,Illumina RCV000381437 SCV000425670 uncertain significance Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000542872 SCV000631585 uncertain significance Ehlers-Danlos syndrome, classic type 2019-07-31 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 88 of the COL5A2 protein (p.Pro88His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs149877855, ExAC 0.02%), 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 COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213134). 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.
Illumina Clinical Services Laboratory,Illumina RCV001142046 SCV001302444 likely benign Ehlers-Danlos syndrome classic type 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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