ClinVar Miner

Submissions for variant NM_000190.4(HMBS):c.601C>T (p.Arg201Trp) (rs118204109)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000432186 SCV000516851 likely pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing The R201W variant in the HMBS gene has been reported previously in association with acute intermittent porphyria (Lundin et al., 1994; Chen et al., 1994). The R201W variant is observed in 4/148,664 (0.0027%) global alleles in large population cohorts (Lek et al., 2016). The R201W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Functional studies in E. coli demonstrate a damaging effect with an unstable protein and reduced enzyme activity (Chen et al., 1994). We interpret R201W as a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000001527 SCV000915504 pathogenic Acute intermittent porphyria 2018-12-18 criteria provided, single submitter clinical testing 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.
Invitae RCV000432186 SCV000955273 pathogenic not provided 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 201 of the HMBS protein (p.Arg201Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with acute intermitent porphyria in a family (PMID: 8270256) and in multiple unrelated individuals affected with this condition (PMID: 7962538, 26075277). ClinVar contains an entry for this variant (Variation ID: 1462). This variant has been reported to affect HMBS protein function (PMID: 7962538, 11055586). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001527 SCV000021682 pathogenic Acute intermittent porphyria 1994-01-01 no assertion criteria provided literature only

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