Submissions for variant NM_000187.4(HGD):c.1102A>G (p.Met368Val)

gnomAD frequency: 0.00031  dbSNP: rs120074173

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000003323	SCV000485142	pathogenic	Alkaptonuria	2015-12-18	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000003323	SCV000538042	pathogenic	Alkaptonuria	2015-08-25	criteria provided, single submitter	clinical testing	The c.1102A>G, p.Met368Val variant was observed to segregate with the disease in multiple affected families [Beltrán-Valero de Bernabé D et al., (1998); Vilboux T et al., (2009)]. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [Vilboux T et al., (2009)]. The M368 residue is close to the active site of the enzyme and is located in a domain called the RmlC-like jelly roll fold. Furthermore, in an enzyme kinetics assay, this variant showed decreased activity (37% of the wild-type), reduced catalytic efficiency (14% of wild-type) and disrupted hydrophobic contacts between subunits in the trimeric assembly [Rodríguez JM et al., (2000)]. Several computational algorithms predicted a damaging effect of this variant on the protein. The frequency of this variant is below the disease-allele frequency in the population databases [1000Genome, Exome Sequencing Project and ExAC]. In summary, the evidence meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing.
Fulgent Genetics, Fulgent Genetics	RCV000003323	SCV000893627	pathogenic	Alkaptonuria	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000003323	SCV000915983	pathogenic	Alkaptonuria	2018-10-23	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the HGD c.1102A>G (p.Met368Val) missense variant has been identified in 42 individuals with alkaptonuria, including in a homozygous state in eight individuals, in a compound heterozygous state in 32 individuals, and in a heterozygous state in three individuals (Beltrán-Valero de Bernabé et al. 1998; Beltrán-Valero de Bernabé et al. 1999a; Beltrán-Valero de Bernabé et al. 1999b; Felbor et al. 1999; Vilboux et al. 2009; Zatkova et al. 2012). The p.Met368Val variant was absent from at least 78 controls and is reported at a frequency of 0.00037 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Met368Val variant is classified as pathogenic for alkaptonuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003323	SCV000953437	pathogenic	Alkaptonuria	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 368 of the HGD protein (p.Met368Val). This variant is present in population databases (rs120074173, gnomAD 0.04%). This missense change has been observed in individuals with alkaptonuria (PMID: 10340975, 19096913, 19862842). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3173). 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%. Experimental studies have shown that this missense change affects HGD function (PMID: 10482952). For these reasons, this variant has been classified as Pathogenic.
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV002279945	SCV002568851	pathogenic	not provided		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV004584308	SCV002577965	pathogenic	See cases	2022-08-19	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PS4,PM2,PM3
GeneDx	RCV002279945	SCV003919485	pathogenic	not provided	2022-10-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10340975, 19096913, 10465119, 31980526, 31589614, 35110678, 23430897, 25681086, 32158253, 16085442, 33621656, 19862842, 30737480, 33666743, 9529363, 10594001, 10482952, 10205262, 33072517)
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000003323	SCV004806652	pathogenic	Alkaptonuria	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000003323	SCV000023481	pathogenic	Alkaptonuria	1999-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000003323	SCV000086738	not provided	Alkaptonuria		no assertion provided	literature only	Most prevalent pathogenic variant in Europe (excluding the Slovak population)
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV000003323	SCV004100981	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_00097).