Submissions for variant NM_000187.4(HGD):c.752G>A (p.Gly251Asp)

gnomAD frequency: 0.00011  dbSNP: rs781011621

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001150629	SCV001311713	uncertain significance	Alkaptonuria	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001150629	SCV001408582	uncertain significance	Alkaptonuria	2021-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with aspartic acid at codon 251 of the HGD protein (p.Gly251Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs781011621, ExAC 0.1%). This missense change has been observed in individual(s) with akaptonuria (PMID: 25804398). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV001150629	SCV005658860	uncertain significance	Alkaptonuria	2024-03-11	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001150629	SCV005849166	uncertain significance	Alkaptonuria	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.752G>A (p.Gly251Asp) variant in HGD gene has been observed in one Italian individual with akaptonuria (Nemethova et. al., 2016). The mechanism of action associated with this variant is in destabilizing promotor region (Nemethova et. al., 2016). The p.Gly251Asp variant is present with allele frequency of 0.01% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on HGD gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 251 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV001150629	SCV004100946	pathogenic	Alkaptonuria		no assertion criteria provided	research	The variant was originally described in AKU patient in PMID:25804398. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00156).