Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000521233 | SCV000621338 | uncertain significance | not provided | 2017-10-09 | criteria provided, single submitter | clinical testing | The R246H variant in the HMBS gene has been reported as a predicted benign variant based on ambiguous in silico predictions and in vitro expression activity (Chen wt al., 2016). The R246H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R246H variant is a conservative amino acid substitution, which at a position that is not conserved. In silico analysis at GeneDx predicts this variant is probably damaging to the protein structure/function. We interpret R246H as a variant of uncertain significance |
Fulgent Genetics, |
RCV000764956 | SCV000896130 | uncertain significance | Acute intermittent porphyria | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000521233 | SCV002165367 | uncertain significance | not provided | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 246 of the HMBS protein (p.Arg246His). This variant is present in population databases (rs201909197, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HMBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 452525). 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 not expected to disrupt HMBS protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HMBS function (PMID: 27539938, 29360981). 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. |