Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002538159 | SCV000953725 | pathogenic | Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3 | 2023-10-15 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 102 of the SDHD protein (p.His102Arg). This variant is present in population databases (rs104894302, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of hereditary paraganglioma-pheochromocytoma syndrome (PMID: 22025150, 30375904, 36614070). ClinVar contains an entry for this variant (Variation ID: 656860). 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 SDHD protein function. This variant disrupts the p.His102 amino acid residue in SDHD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10657297, 12811540, 19454582, 22241717). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV001018360 | SCV001179586 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-04-20 | criteria provided, single submitter | clinical testing | The p.H102R variant (also known as c.305A>G), located in coding exon 3 of the SDHD gene, results from an A to G substitution at nucleotide position 305. The histidine at codon 102 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with SDHD-associated disease (Poeppel TD et al. J. Clin. Oncol. 2011 Nov;29(33):e812-5; Shulskaya MV et al. Int. J. Neurosci. 2018 Dec;128(12):1174-1179; Kudryavtseva AV et al. BMC Med Genomics 2019 Mar;12(Suppl 2):39; Pavlov VS et al. BMC Med Genomics, 2020 09;13:125). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |