Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000432186 | SCV000516851 | likely pathogenic | not provided | 2019-11-15 | criteria provided, single submitter | clinical testing | 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) |
| Illumina Laboratory Services, |
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 | 2023-08-03 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs118204109, gnomAD 0.01%). 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). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HMBS function (PMID: 7962538, 11055586). 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 HMBS protein function. ClinVar contains an entry for this variant (Variation ID: 1462). 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. |
| Mayo Clinic Laboratories, |
RCV000432186 | SCV004226625 | likely pathogenic | not provided | 2022-06-23 | criteria provided, single submitter | clinical testing | PP3, PP4, PM2, PS3 |
| OMIM | RCV000001527 | SCV000021682 | pathogenic | Acute intermittent porphyria | 1994-01-01 | no assertion criteria provided | literature only |