ClinVar Miner

Submissions for variant NM_000346.4(SOX9):c.508C>T (p.Pro170Ser) (rs866706988)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000677668 SCV000803808 likely pathogenic Camptomelic dysplasia 2017-06-23 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853284 SCV000996119 pathogenic Campomelic dysplasia with autosomal sex reversal 2018-03-26 criteria provided, single submitter clinical testing This variant has been previously reported in an individual with multiple congenital anomalies (PMID: 26633542). Different missense variants affecting the same amino acid residue (p.Pro170Leu, p.Pro170Arg) have been reported in patients with acampomelic and campomelic dyplasia respectively (PMID: 19921652; 9002675). The p.Pro170Ser variant detected in this individual is absent from the ExAC and gnomAD population databases. It occurs at a highly conserved amino acid and is predicted by multiple in silico tools to be damaging to protein function. Based on the available evidence, the p.Pro170Ser variant in SOX9 is classified as a pathogenic change.
Invitae RCV000677668 SCV001405520 uncertain significance Camptomelic dysplasia 2019-08-10 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 170 of the SOX9 protein (p.Pro170Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in at least one individual affected with multiple congenital anomalies (PMID: 26633542). ClinVar contains an entry for this variant (Variation ID: 559879). 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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