Submissions for variant NM_000187.4(HGD):c.680T>C (p.Phe227Ser)

dbSNP: rs1941093400

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037383	SCV001200794	pathogenic	Alkaptonuria	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 227 of the HGD protein (p.Phe227Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with alkaptonuria (PMID: 9529363, 21437689; Invitae). This variant is also known as c.847T>C. ClinVar contains an entry for this variant (Variation ID: 836287). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV001037383	SCV004100980	pathogenic	Alkaptonuria		no assertion criteria provided	research	The variant was originally described in AKU patient in PMID:9529363. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00073).