Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000799967 | SCV000939661 | likely pathogenic | not provided | 2022-04-16 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 116 of the HMBS protein (p.Arg116Gln). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with acute intermittent porphyria (PMID: 8081367). ClinVar contains an entry for this variant (Variation ID: 645809). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p. Arg116 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8096492, 9281416, 19656453, 23815679). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Illumina Laboratory Services, |
RCV001107356 | SCV001264498 | uncertain significance | Acute intermittent porphyria | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |