ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.716_719del (p.Ser239fs) (rs587781266)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128877 SCV000172734 pathogenic Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing The c.716_719delCTCT pathogenic mutation, located in coding exon 7 of the SDHB gene, results from a deletion of 4 nucleotides at nucleotide positions 716 to 719, causing a translational frameshift with a predicted alternate stop codon (p.S239Yfs*8). This alteration has previously been detected in individuals diagnosed with pheochromocytoma and paraganglioma (Neumann HP et al. N Engl J Med. 2002 May 9;346(19):1459-66; Vanharanta S et al. Am J Hum Genet. 2004 Jan;74(1):153-9). Of note, this alteration is also designated as 847delTCTC and c.847_50delTCTC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001034689 SCV000644766 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-01-13 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 7 of the SDHB mRNA (c.716_719delCTCT), causing a frameshift at codon 239. This creates a premature translational stop signal in the penultimate exon of the SDHB mRNA (p.Ser239Tyrfs*8). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid residues of the SDHB protein. This variant is not present in population databases (rs587781266, ExAC no frequency). This variant has been reported in individuals affected with pheochromocytoma (PMID: 15328326) and to segregate with paraganglioma and renal cell carcinoma in a single family (PMID: 14685938). This variant is also known as 847delTCTC and c.847-50delTCTC in the literature. ClinVar contains an entry for this variant (Variation ID: 12782). Several missense substitutions at codon 242 (p.Arg242His, p.Arg242Cys, and p.Arg242Ser) have been determined to be pathogenic (PMID: 25972245, 25736212, 23175444, 23175444). This suggests that the arginine residue is critical for SDHB protein function and that other variants that disrupt this position, including this frameshift variant, are also pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013621 SCV000033868 pathogenic Paragangliomas 4 2002-05-09 no assertion criteria provided literature only
OMIM RCV000013622 SCV000033869 pathogenic Pheochromocytoma 2002-05-09 no assertion criteria provided literature only

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