Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute for Genomic Medicine |
RCV000467345 | SCV007449340 | pathogenic | Pheochromocytoma/paraganglioma syndrome 3 | 2023-09-13 | criteria provided, single submitter | clinical testing | This variant is predicted to result in loss of function through nonsense-mediated decay of the encoded transcript or premature truncation of the encoded protein in a gene in which loss of function is a known mechanism of disease (ACMG/AMP: PVS1_Strong). This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4; PMIDs:16249420, 19351833, 19454582, 22517554, 23282968). This variant is absent from or present at an exceedingly low frequency in gnomAD, a large-scale control population database (ACMG/AMP: PM2). |
| Myriad Genetics, |
RCV000467345 | SCV004018724 | pathogenic | Pheochromocytoma/paraganglioma syndrome 3 | 2024-02-15 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30201732, 30877234, 16249420, 11062460, 25720320]. |
| Gene |
RCV001559453 | SCV001781683 | pathogenic | not provided | 2025-02-11 | criteria provided, single submitter | clinical testing | Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19454582, 22517557, 27011036, 23282968, 19351833, 28748451, 16249420, 31589614, 33087929, 34558728, 24096523, 31447099, 22517554, 22351710, 11062460, 34750850, 30201732, 30877234) |
| New York Genome Center | RCV000467345 | SCV001622967 | pathogenic | Pheochromocytoma/paraganglioma syndrome 3 | 2020-07-17 | criteria provided, single submitter | clinical testing | The variant c.1A>G affects the initiator methionine of the SDHC mRNA. This variant is present in population databases (gnomAD v30.001%) and has been reported in the literature in 3 individuals affected with paraganglioma/pheochromocytoma and gastrointestinal stromal tumors [PMID: 23282968; PMID: 22517554; PMID: 19454582], and in a family with Paraganglioma Syndrome [PMID: 16249420]. Two different variants (c.2T>A and c.3G>A) that disrupt the same methionine initiator have been reported in patients and families affected with head and neck paragangliomas [PMID: 19351833], paragangliomas [PMID: 11062460], and renal cell carcinoma [PMID: 22351710], indicating that this methionine initiator of SDHC may be critical for protein function. Based on the available evidence, this variant has been classified as Pathogenic. |
| Human Genome Sequencing Center Clinical Lab, |
RCV000467345 | SCV001434947 | pathogenic | Pheochromocytoma/paraganglioma syndrome 3 | 2018-10-12 | criteria provided, single submitter | clinical testing | This rare c.1A>G (p.Met1?) variant (seen once in gnomAD) in the SDHC gene is predicted to result in a start codon loss of the major biological transcripts. The variant has been observed in multiple unrelated individuals paraganglioma/pheochromocytoma (PMID 16249420, 19351833, 19454582). Predicted start codon loss with different nucleotide changes in this gene has been also observed in other individuals with paraganglioma (PMID : 19351833) . Therefore, this c.1A>G (p.Met1?) variant variant is considered as pathogenic. |
| Center for Human Genetics, |
RCV000467345 | SCV000782281 | pathogenic | Pheochromocytoma/paraganglioma syndrome 3 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000492170 | SCV000581217 | pathogenic | Hereditary cancer-predisposing syndrome | 2025-06-03 | criteria provided, single submitter | clinical testing | The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the SDHC gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This mutation has previously been reported in multiple individuals diagnosed with paragangliomas (Niemann S et al. Nat Genet 2000 Nov;26(3):268-70; Schiavi F et al. JAMA. 2005 Oct;294:2057-63; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6; Am J Surg Pathol 2013 Feb;37(2):234-40). The mutation was also detected in an individual whose GIST tumor showed a loss of SDHB expression and intact SDHA expression on IHC (Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV000791400 | SCV000546039 | pathogenic | Gastrointestinal stromal tumor; Pheochromocytoma/paraganglioma syndrome 3 | 2025-12-13 | criteria provided, single submitter | clinical testing | This sequence change affects the initiator codon of the SDHC mRNA. This change may impact translation initiation or efficiency. The next in-frame methionine is located at codon 38. This variant is present in population databases (rs755235380, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with clinical features of SDHC-related conditions (PMID: 11062460, 16249420, 19454582, 22351710, 22517554, 23282968). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 407060). For these reasons, this variant has been classified as Pathogenic. |