rs118204109
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000190.4(HMBS):c.601C>T(p.Arg201Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,550,004 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 Likely pathogenic (★★).
Frequency
Consequence
NM_000190.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000256 AC: 4AN: 155962Hom.: 0 AF XY: 0.0000365 AC XY: 3AN XY: 82192
GnomAD4 exome AF: 0.0000143 AC: 20AN: 1397758Hom.: 0 Cov.: 30 AF XY: 0.0000145 AC XY: 10AN XY: 689526
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74386
ClinVar
Submissions by phenotype
Acute intermittent porphyria Pathogenic:3
PM2_Supporting+PS3_Moderate+PS4_Moderate+PP4 -
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The HMBS c.601C>T (p.Arg201Trp) missense variant has been reported in at least four studies in which it was found in a heterozygous state in at least 12 individuals with acute intermittent porphyria or hydroxymethylbilane synthase deficiency.(Lundin et al. 1994; Chen et al. 1994; Floderus et al. 2002; Cerbino et al. 2015). At least seven of these individuals were from one family in which the variant displayed segregation with disease (Lundin et al. 1994). Control data are unavailable for the p.Arg201Trp variant, which is reported at a frequency of 0.000027 in the total population of the Genome Aggregation Database. Functional studies conducted in E. coli indicate the variant form of the protein exhibited reduced enzymatic activity and stability compared to the wild type (Chen et al. 1994). Based on the collective evidence, the p.Arg201Trp variant is classified as pathogenic for hydroxymethylbilane synthase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided Pathogenic:3
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12372055, 7962538, 8270256, 26075277, 11055586) -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 201 of the HMBS protein (p.Arg201Trp). This variant is present in population databases (rs118204109, gnomAD 0.01%). This missense change has been observed in individual(s) with acute intermitent porphyria (PMID: 7962538, 8270256, 26075277). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1462). 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 HMBS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HMBS function (PMID: 7962538, 11055586). For these reasons, this variant has been classified as Pathogenic. -
PP3, PP4, PM2, PS3 -
Encephalopathy, porphyria-related Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at