Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000799514 | SCV000939179 | pathogenic | not provided | 2023-07-06 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 645443). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg26 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8401516, 9238757, 9281416, 18627369, 19292878, 19656452, 20978940). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HMBS function (PMID: 11055586, 19292878). 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. This missense change has been observed in individuals with acute intermittent porphyria (PMID: 7757070, 9199558, 10502788, 11831862, 16817012, 18627369, 19292878, 20978940, 24997713). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 26 of the HMBS protein (p.Arg26Cys). |
| Mayo Clinic Laboratories, |
RCV000799514 | SCV002525805 | pathogenic | not provided | 2021-11-01 | criteria provided, single submitter | clinical testing | PP3, PP4, PM2, PM5, PS4 |
| 3billion, |
RCV003152734 | SCV003841778 | pathogenic | Acute intermittent porphyria | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11055586, 16025832). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000645443) and different missense changes at the same codon (p.Arg26His, p.Arg26Leu / ClinVar ID: VCV000001443, VCV000665873) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Genomic Medicine Center of Excellence, |
RCV003152734 | SCV004807659 | likely pathogenic | Acute intermittent porphyria | 2024-03-29 | criteria provided, single submitter | clinical testing |