chr3-120633233-T-C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000187.4(HGD):c.1102A>G(p.Met368Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000187.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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HGD | NM_000187.4 | c.1102A>G | p.Met368Val | missense_variant | Exon 13 of 14 | ENST00000283871.10 | NP_000178.2 | |
HGD | XM_005247412.3 | c.877A>G | p.Met293Val | missense_variant | Exon 11 of 12 | XP_005247469.1 | ||
HGD | XM_017006277.3 | c.679A>G | p.Met227Val | missense_variant | Exon 13 of 14 | XP_016861766.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HGD | ENST00000283871.10 | c.1102A>G | p.Met368Val | missense_variant | Exon 13 of 14 | 1 | NM_000187.4 | ENSP00000283871.5 | ||
HGD | ENST00000470321.1 | n.442A>G | non_coding_transcript_exon_variant | Exon 3 of 3 | 3 | |||||
HGD | ENST00000492108.5 | n.*84A>G | non_coding_transcript_exon_variant | Exon 5 of 6 | 2 | ENSP00000419838.1 | ||||
HGD | ENST00000492108.5 | n.*84A>G | 3_prime_UTR_variant | Exon 5 of 6 | 2 | ENSP00000419838.1 |
Frequencies
GnomAD3 genomes AF: 0.000335 AC: 51AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000167 AC: 42AN: 251288Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135798
GnomAD4 exome AF: 0.000196 AC: 287AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.000195 AC XY: 142AN XY: 727240
GnomAD4 genome AF: 0.000335 AC: 51AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26AN XY: 74454
ClinVar
Submissions by phenotype
Alkaptonuria Pathogenic:8Other:1
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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). -
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 [RodrÃguez 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. -
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Most prevalent pathogenic variant in Europe (excluding the Slovak population) -
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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. -
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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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HGD protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HGD function (PMID: 10482952). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:3
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) -
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See cases Pathogenic:1
ACMG categories: PS1,PS4,PM2,PM3 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at