ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.423+1G>A (rs398122805)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163600 SCV000214164 pathogenic Hereditary cancer-predisposing syndrome 2018-05-11 criteria provided, single submitter clinical testing ​The c.423+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the SDHB gene. This mutation is a known Dutch founder mutation and it has been reported in numerous Dutch families with hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndrome (Hensen EF et al. Clin Genet. 2012 Mar;81(3):284-8; Rijken JA et al. Clin. Genet. 2018 Jan;93(1):60-66). In addition, this mutation has been reported in other individuals with PGL-PCC in the literature (Erlic et al. Clin Cancer Res. 2009; 15: 6378; Gill AJ et al. Am. J. Surg. Pathol. 2011 Oct; 35(10):1578-85). It was also identified as a de novo occurrence in a 6-year-old patient with an abdominal paraganglioma (Imamura H et al. Eur. J. Pediatr. 2016 Jan;175(1):137-41). One study from the Netherlands identified this mutation in two individuals with sporadic PGL and cDNA analysis by RT-PCR showed that this mutation abolished the native donor splice site, leading to a 54 nucleotide deletion resulting in the in-frame deletion of 18 amino acids (Bayley JP et al. BMC Med Genet. 2006 Jan 11;7:1). Authors of one study questioned if this mutation may show reduced penetrance because it was detected in both asymptomatic individuals and individuals diagnosed with PGL in one Dutch family. The family history also included ganglioneuroma, rectal cancer, ovarian cancer, endometrial cancer, and breast cancer (Hes FJ et al. BMC Med Genet. 2010 Jun 11;11:92). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000627750 SCV000287775 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-09-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the SDHB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs398122805, ExAC 0.001%). This variant has been reported in individuals with paraganglioma (PGL) and/or pheochromocytoma (PCC), and shown to segregate with disease in two families (PMID: 16405730, 20540712, 21348866, 19411806, 19825962, 25047027). This variant is also commonly found in Dutch patients with PGL/PCC (PMID: 16405730, 21348866, 25047027). ClinVar contains an entry for this variant (Variation ID: 29896). Analysis of mRNA in affected patients demonstrated that this variant leads to the utilization of a cryptic splice site 54 nucleotides upstream of the original donor splice site and exclusion of 18 amino acids from the translated protein (PMID: 16405730, 19411806). Experimental studies testing the functional impact of this in-frame deletion have not been reported. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000481826 SCV000565545 pathogenic not provided 2018-01-02 criteria provided, single submitter clinical testing This variant is denoted SDHB c.423+1G>A or IVS4+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 4 of the SDHB gene. This variant destroys a canonical splice donor site and has been shown to result in the use of an alternate splice site 54 base pairs upstream in exon 4, resulting in an in-frame deletion of 18 amino acids within the 2Fe-2S ferredoxin-type domain (Bayley 2006, Ercolino 2009, UniProt). This variant has been published in multiple individuals with a personal history of tumors related to the Hereditary Paraganglioma-Pheochromocytoma syndrome, many of which are reported to show absence of the SDHB protein via immunohistochemistry (Bayley 2006, Benn 2006, Burnichon 2009, Casc?n 2009, Ercolino 2009, Erlic 2009, Meyer-Rochow 2009, Hes 2010, Gill 2011, Hensen 2012, Heesterman 2013, Gill 2014, van Hulsteijn 2014, Curr?s-Freixes 2015, D?nes 2015, Niemeijer 2015, Sue 2015, Imamura 2016). SDHB c.423+1G>A has been shown to segregate with disease in families (Hes 2010, Gill 2011) and has been reported as a founder variant in the Dutch population (Hesen 2012, Heesterman 2013, van Hulsteijn 2014). While some studies of this population have suggested that this variant may have reduced penetrance compared to other SDHB pathogenic variants, other studies did not demonstrate a difference in penetrance (Hes 2010, van Hulsteijn 2014, Rijken 2017). Based on the currently available evidence, we consider SDHB c.423+1G>A to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508053 SCV000605077 pathogenic none provided 2019-12-19 criteria provided, single submitter clinical testing The SDHB c.423+1G>A variant (rs398122805) is described in the medical literature in individuals and families with paraganglioma and pheochromocytoma (Bayley 2006, Ercolino 2009, Erlic 2009, Hensen 2012, Hes 2010). The variant has also been shown to have reduced penetrance (Hes 2010). The variant is described in the ClinVar database (Variation ID: 29896) and in the Genome Aggregation Database in 3 out of 251,374 alleles. This variant occurs in the conserved splicing signal and has been shown to result in an in-frame deletion of 18 amino acids (Ercolino 2009). Considering available information, this variant is classified as pathogenic. References: Bayley JP et al. Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma. BMC Med Genet. 2006 7:1. Ercolino T et al. Malignant extra-adrenal pheochromocytoma caused by an SDHB intronic variation leading to a 54-bp deletion in exon 4. J Endocrinol Invest. 2009 32(2):111-4. Erlic Z et al. Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients. Clin Cancer Res. 2009 15(20):6378-85. Hensen EF et al. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin Genet. 2012 Mar;81(3):284-8. Hes FJ et al. Low penetrance of a SDHB mutation in a large Dutch paraganglioma family. BMC Med Genet. 2010 11:92.
Fulgent Genetics,Fulgent Genetics RCV000762867 SCV000893247 pathogenic Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000022779 SCV000044068 pathogenic Paragangliomas 4 2012-03-01 no assertion criteria provided literature only
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505379 SCV000599500 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000481826 SCV001809253 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000481826 SCV001927436 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000481826 SCV001955480 pathogenic not provided no assertion criteria provided clinical testing

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