Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000222241 | SCV000274333 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-02-28 | criteria provided, single submitter | clinical testing | The p.D74A pathogenic mutation (also known as c.221A>C), located in coding exon 3 of the SDHB gene, results from an A to C substitution at nucleotide position 221. The aspartic acid at codon 74 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHB-related disease and co-segregated with disease in at least one family (Greenberg SE et al. Clin Endocrinol (Oxf), 2021 Sep;95:447-452; Ambry internal data; personal communication). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV000475368 | SCV000554041 | pathogenic | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 74 of the SDHB protein (p.Asp74Ala). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with paraganglioma (PGL), gastrointestinal stromal tumor, and renal cell carcinoma including SDH-deficient tumors ( (Invitae; external communications). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 230694). 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 expected to disrupt SDHB protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV001551663 | SCV000605079 | likely pathogenic | not provided | 2022-02-11 | criteria provided, single submitter | clinical testing | The SDHB c.221A>C; p.Asp74Ala variant (rs876658713) is reported in the literature in an individual affected with hereditary paraganglioma-pheochromocytoma syndrome (Greenberg 2020). This variant has also been observed in multiple patients affected with paraganglioma and renal cell carcinoma including SDH-deficient tumors at ARUP and other laboratories (external communications). This variant is also reported in ClinVar (Variation ID: 230694), but is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartate at codon 74 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.939). Based on available information, this variant is considered to be likely pathogenic. References: Greenberg SE et al. Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome. Genet Med. 2020 Dec;22(12):2101-2107. PMID: 32741965. |
| Gene |
RCV001551663 | SCV001772221 | pathogenic | not provided | 2022-06-14 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals undergoing screening for Hereditary PGL/PCC syndrome in published literature (Greenberg 2020); This variant is associated with the following publications: (PMID: 32741965) |
| Baylor Genetics | RCV003475010 | SCV004202995 | likely pathogenic | Gastrointestinal stromal tumor | 2024-02-19 | criteria provided, single submitter | clinical testing | |
| Human Genome Sequencing Center Clinical Lab, |
RCV004556769 | SCV005045795 | likely pathogenic | Paragangliomas 4 | 2023-11-16 | criteria provided, single submitter | clinical testing | The c.221A>C (p.Asp74Ala) variant in the SDHB gene is located on the exon 3 and is predicted to replace aspartic acid with alanine at codon 74 (p.Asp74Ala). The variant has been reported in individuals with paraganglioma/pheochromocytoma (PMID: 34255389, 34906457). The variant is reported to segregate with diseease by several ClinVar submitters (ID: 230694). The variant is rare in general population according to gnomAD (1/251336). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.939). Therefore, the c.221A>C (p.Asp74Ala) variant of SDHB has been classified as likely pathogenic. |