Submissions for variant NM_000346.4(SOX9):c.508C>G (p.Pro170Ala)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001291597	SCV001480146	likely pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001329809	SCV001521346	likely pathogenic	Camptomelic dysplasia		criteria provided, single submitter	clinical testing
Institute of Human Genetics, Heidelberg University	RCV001329809	SCV001739384	pathogenic	Camptomelic dysplasia	2021-04-21	criteria provided, single submitter	clinical testing	The variant was not found in DNA extracted from the parents' blood samples (PS2), the variant is absent from controls (gnomAD; PM2), multiple lines of computational evidence support a deleterious effect (PP3) and it is localized at an amino acid site where different missense changes determined to be pathogenic have been seen before (PM5); therefore we classified it as pathogenic according to ACMG criteria.
Invitae	RCV001329809	SCV002259073	likely pathogenic	Camptomelic dysplasia	2022-06-20	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro170 amino acid residue in SOX9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9002675). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOX9 protein function. ClinVar contains an entry for this variant (Variation ID: 996802). This variant has not been reported in the literature in individuals affected with SOX9-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 170 of the SOX9 protein (p.Pro170Ala).

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