Submissions for variant NM_000187.4(HGD):c.8A>C (p.Glu3Ala)

gnomAD frequency: 0.00022  dbSNP: rs200412910

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671567	SCV000796555	uncertain significance	Alkaptonuria	2017-12-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000671567	SCV001310176	uncertain significance	Alkaptonuria	2017-04-28	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.
Fulgent Genetics, Fulgent Genetics	RCV000671567	SCV002786351	uncertain significance	Alkaptonuria	2022-02-11	criteria provided, single submitter	clinical testing
Invitae	RCV000671567	SCV003290355	uncertain significance	Alkaptonuria	2022-07-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 3 of the HGD protein (p.Glu3Ala). This variant is present in population databases (rs200412910, gnomAD 0.07%). This missense change has been observed in individual(s) with alkaptonuria (PMID: 19862842). ClinVar contains an entry for this variant (Variation ID: 555702). 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 not expected to disrupt HGD protein function. 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.
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV000671567	SCV004101011	pathogenic	Alkaptonuria		no assertion criteria provided	research	The variant was originally described in AKU patient in PMID:19862842. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00001).