ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.423+1G>A (rs398122805)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508053 SCV000605077 pathogenic not specified 2017-03-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163600 SCV000214164 pathogenic Hereditary cancer-predisposing syndrome 2017-03-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Fulgent Genetics,Fulgent Genetics RCV000762867 SCV000893247 pathogenic Paraganglioma and gastric stromal sarcoma; Paragangliomas 4; Pheochromocytoma 2018-10-31 criteria provided, single submitter clinical testing
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.
Invitae RCV000627750 SCV000287775 pathogenic Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-12-10 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.
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

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