Submissions for variant NM_000187.4(HGD):c.157C>T (p.Arg53Trp)

gnomAD frequency: 0.00001  dbSNP: rs759435977

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001242145	SCV001415213	likely pathogenic	Alkaptonuria	2022-06-02	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 53 of the HGD protein (p.Arg53Trp). This variant is present in population databases (rs759435977, gnomAD 0.003%). This missense change has been observed in individual(s) with HGD-related conditions (PMID: 11001939, 16085442, 19862842; Invitae). ClinVar contains an entry for this variant (Variation ID: 967274). 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. This variant disrupts the p.Arg53 amino acid residue in HGD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25681086, 25804398). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Genomics England Pilot Project, Genomics England	RCV001242145	SCV001760101	likely pathogenic	Alkaptonuria		no assertion criteria provided	clinical testing
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV001242145	SCV004101014	pathogenic	Alkaptonuria		no assertion criteria provided	research	The variant was originally described in AKU patient in PMID:11001939. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00011).