Submissions for variant NM_000187.4(HGD):c.343G>C (p.Gly115Arg)

gnomAD frequency: 0.00001  dbSNP: rs755734596

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NxGen MDx	RCV001542260	SCV001760925	likely pathogenic	Alkaptonuria	2019-12-09	criteria provided, single submitter	clinical testing	This missense variant (c.343G>C) affects the 3rd nucleotide in the final amino acid in exon 6 of HGD, which is a hotspot (PM1). The equivalent amino-acid variant Gly115Arg (chr3:120369710 GCC⇒CCT) is classified pathogenic and associated with Alkaptonuria by UniProt based on a clinical report in Usher et al. (PMID 25681086) in 2 cases with 2nd allele K431fs and M368V respectively. In silico models produced pathogenic predictions (PP3). This variant is not found in gnomAD databases (PM2) and this region of HGD has a low rate of benign missense variation (PP2). This variant was first reported by Zatkova et al. in 2012 (PMID 23430897) in 1 case with no 2nd allele information. We interpret c.343G>C to be likely pathogenic.
Invitae	RCV001542260	SCV002254885	likely pathogenic	Alkaptonuria	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 115 of the HGD protein (p.Gly115Arg). This variant is present in population databases (rs755734596, gnomAD 0.002%). This missense change has been observed in individual(s) with alkaptonuria (PMID: 21720873, 25681086; Invitae). ClinVar contains an entry for this variant (Variation ID: 1184269). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV001542260	SCV004098945	pathogenic	Alkaptonuria		no assertion criteria provided	research	The variant was described in AKU patient in PMID:23430897. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00146).