Submissions for variant NM_000187.4(HGD):c.674G>C (p.Arg225Pro)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003388986	SCV004293140	likely pathogenic	Alkaptonuria	2022-12-08	criteria provided, single submitter	clinical testing	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 HGD protein function. 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.Arg225 amino acid residue in HGD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12872836, 25681086). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This missense change has been observed in individuals with Alkaptonuria (PMID: 25681086). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 225 of the HGD protein (p.Arg225Pro).
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV003388986	SCV004100949	pathogenic	Alkaptonuria		no assertion criteria provided	research	The variant was originally described in AKU patients in PMID: 25681086. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00AKU_00170).