Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics, |
RCV002225205 | SCV002503765 | likely pathogenic | Acute intermittent porphyria | 2022-08-12 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace aspartic acid with tyrosine at codon 61 of the HMBS protein, p.(Asp61Tyr). The aspartic acid residue is highly conserved (100 vertebrates, UCSC), and is located at the start of a helix in the porphobilinogen deaminase, dipyromethane cofactor binding domain. There is a large physicochemical difference between aspartic acid and tyrosine. The variant is absent in a large population cohort (gnomAD v2.1). It has been identified in at least three unrelated probands with a clinical diagnosis of acute intermittent porphyria (AIP; PMID: 11857754, Royal Melbourne Hospital). Furthermore, the porphyrin precursor biochemical results measured during acute attacks for a case with the variant are said to confirm a clinical diagnosis of AIP and a defect in the HMBS gene (Royal Melbourne Hospital). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Additionally, substitutions to histidine and asparagine at this position (p.Asp61His, p.Asp61Asn) have been identified in AIP patients. Based on the classification scheme RMH ACMG Guidelines v1.1.1 and recommendations from the International Porphyria Molecular Diagnostic Collaborative (PMID: 31073229), this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PP4_Moderate, PS4_Supporting, PP3. |