Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV001108005 | SCV001265199 | uncertain significance | Acute intermittent porphyria | 2017-04-28 | 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. |
| Invitae | RCV001862867 | SCV002160883 | uncertain significance | not provided | 2022-01-19 | criteria provided, single submitter | clinical testing | This variant disrupts the p.His256 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been observed in individuals with HMBS-related conditions (PMID: 1427766, 9199558), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not substantially affect HMBS function (PMID: 27539938). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 880030). This variant has not been reported in the literature in individuals affected with HMBS-related conditions. This variant is present in population databases (rs758794172, gnomAD 0.004%). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 256 of the HMBS protein (p.His256Gln). |