Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000489906 | SCV000577609 | pathogenic | not provided | 2019-09-21 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect on enzyme kinetics, resulting in 1-5% of normal enzyme activity and leading to an accumulation of porphyrin precursors (Bustad et al., 2013; Solis et al., 2004; Chen et al., 2016).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11202057, 1577472, 15534187, 23815679, 12699244, 27539938, 11055586, 1301948, 2243128, 15643298, 15003823, 1496994) |
| Invitae | RCV000489906 | SCV000944323 | pathogenic | not provided | 2023-10-06 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 167 of the HMBS protein (p.Arg167Trp). This variant is present in population databases (rs118204101, gnomAD 0.02%). This missense change has been observed in individuals with acute intermittent porphyria (PMID: 1496994, 1577472, 15003823, 15534187, 15643298, 23815679). ClinVar contains an entry for this variant (Variation ID: 1456). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HMBS function (PMID: 1496994, 11055586, 23815679, 27539938). This variant disrupts the p.Arg167 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1496994, 1577472, 2243128, 7962538, 9199558, 12372055, 15003823, 15643298, 23815679). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Revvity Omics, |
RCV000001521 | SCV003822772 | pathogenic | Acute intermittent porphyria | 2021-11-24 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000001521 | SCV000021676 | pathogenic | Acute intermittent porphyria | 2004-11-01 | no assertion criteria provided | literature only | |
| OMIM | RCV003764512 | SCV004697361 | pathogenic | Encephalopathy, porphyria-related | 2004-11-01 | no assertion criteria provided | literature only |