Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000226466 | SCV000287789 | pathogenic | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2024-01-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 242 of the SDHB protein (p.Arg242Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma (PMID: 19351833; Invitae). ClinVar contains an entry for this variant (Variation ID: 239443). 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 SDHB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 23175444). This variant disrupts the p.Arg242 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19351833, 21173220, 22517554). 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 | RCV000492633 | SCV000581213 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-03-22 | criteria provided, single submitter | clinical testing | The p.R242S pathogenic mutation (also known as c.724C>A), located in coding exon 7 of the SDHB gene, results from a C to A substitution at nucleotide position 724. The arginine at codon 242 is replaced by serine, an amino acid with dissimilar properties. This alteration was reported in 2/578 individuals with head and neck paragangliomas (Neumann HP et al. Cancer Res. 2009 Apr;69(8):3650-6). In addition, a different disease causing mutation, p.R242H, has been described at this position (Kim E et al. Endocr. Relat. Cancer. 2015 Jun; 22(3):387-97). Functional studies using yeast models determined that the yeast-equivalent alteration of p.R242S, yR235S, results in an OXPHOS phenotype similar to the null strain; with no detectable SDH activity, 50% reduction in respiration, and increased genomic instability (Panizza E et al. Hum. Mol. Genet. 2013 Feb;22(4):804-15). 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 available evidence, this alteration is classified as a pathogenic mutation. |
Gene |
RCV000523546 | SCV000616875 | pathogenic | not provided | 2024-02-15 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: defective SDH enzyme activity and increased mtDNA mutability and sensitivity to oxidative stress (PMID: 23175444); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25972245, 19351833, 22904323, 30787465, 31492822, 34377882, 34906457, 23175444) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323466 | SCV004029460 | pathogenic | Hereditary pheochromocytoma-paraganglioma | 2023-07-17 | criteria provided, single submitter | clinical testing | Variant summary: SDHB c.724C>A (p.Arg242Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes. c.724C>A has been reported in the literature in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (e.g. Neumann_2009, Siddiqui_2021, Garrett_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in undetectable SDH enzyme activity in vitro (e.g. Panizza_2013). The following publications have been ascertained in the context of this evaluation (PMID: 34906457, 19351833, 23175444, 34377882). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Color Diagnostics, |
RCV003514330 | SCV004362268 | pathogenic | Paragangliomas 4 | 2023-03-01 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with serine at codon 242 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in yeast have shown that this variant signifiantly affected SDH activity and mitochondrial respiration, increasing of mtDNA mutability and sensitivity to oxidative stress. The variant disrupts a functionally important LYR motif. (PMID: 23175444, 26719882). This variant has been reported in individuals affected with paragangliomas and/or pheochromocytomas (PMID: 19351833, 34377882, 34906457, 35870552). Other variants at this position are considered disease causing (ClinVar Variation ID: VCV000012781, VCV000186827). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
All of Us Research Program, |
RCV003323466 | SCV005424050 | pathogenic | Hereditary pheochromocytoma-paraganglioma | 2024-09-28 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with serine at codon 242 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in yeast have shown that this variant signifiantly affected SDH activity and mitochondrial respiration, increasing of mtDNA mutability and sensitivity to oxidative stress. The variant disrupts a functionally important LYR motif. (PMID: 23175444, 26719882). This variant has been reported in individuals affected with paragangliomas and/or pheochromocytomas (PMID: 19351833, 34377882, 34906457, 35870552). Other variants at this position are considered disease causing (ClinVar Variation ID: VCV000012781, VCV000186827). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
Prevention |
RCV004732806 | SCV005344238 | pathogenic | SDHB-related disorder | 2024-04-05 | no assertion criteria provided | clinical testing | The SDHB c.724C>A variant is predicted to result in the amino acid substitution p.Arg242Ser. This variant has been repeatedly reported in individuals with paraganglioma (see for example, Neumann et al. 2009. PubMed ID: 19351833, Suppl. Table 1; Panizza et al. 2012. PubMed ID: 23175444; Siddiqui et al. 2021. PubMed ID: 34377882; Garrett et al. 2021. PubMed ID: 34906457, Supplementary Table 2). In the Panizza et al. study, the yeast model study showed that this missense change has a severe phenotypic effect. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has been widely interpreted as pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/239443/). This variant is interpreted as pathogenic. |