Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV002251059 | SCV002521432 | uncertain significance | Congenital bile acid synthesis defect 1 | 2022-05-22 | 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%). A different missense change at the same codon (p.Arg228Gln) has been reported to be associated with HSD3B7 related disorder (PMID: 26712441). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. |
| Invitae | RCV003669256 | SCV004391107 | pathogenic | not provided | 2023-03-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg228 amino acid residue in HSD3B7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 34627351). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HSD3B7 protein function. ClinVar contains an entry for this variant (Variation ID: 1687377). This missense change has been observed in individual(s) with clinical features of congenital bile acid synthesis defect (PMID: 34627351). This variant is present in population databases (rs746884533, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 228 of the HSD3B7 protein (p.Arg228Trp). |