ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.718_721del (p.Leu240fs) (rs794728950)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183221 SCV000235641 pathogenic not provided 2014-09-16 criteria provided, single submitter clinical testing The c.718_721delCTAT mutation in the SDHB gene has been reported previously in association with pheochromocytoma (Amar et al., 2005). The deletion causes a frameshift starting with codon Leucine 240, changes this amino acid to a Threonine residue and creates a premature Stop codon at position 7 of the new reading frame, denoted p.Leu240ThrfsX7. This mutation is predicted to cause loss of normal protein function through protein truncation. Specifically, the last 41 correct residues are lost and replaced by 6 incorrect residues. The variant is found in the SDHB panel(s).
Ambry Genetics RCV001026125 SCV001188444 pathogenic Hereditary cancer-predisposing syndrome 2019-04-26 criteria provided, single submitter clinical testing The c.718_721delCTAT pathogenic mutation, located in coding exon 7 of the SDHB gene, results from a deletion of 4 nucleotides at nucleotide positions 718 to 721, causing a translational frameshift with a predicted alternate stop codon (p.L240Tfs*7). This alteration has been reported in multiple individuals diagnosed with paragangliomas and/or pheochromocytomas (Amar L et al. J. Clin. Oncol. 2005 Dec;23:8812-8; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Bernardo-Castiñeira C et al. Head Neck 2019 Jan;41:79-91). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001385644 SCV001585578 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-09-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SDHB gene (p.Leu240Thrfs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acids of the SDHB protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of paraganglioma-pheochromocytoma syndromes (PMID: 19454582, 16314641, 30877234). ClinVar contains an entry for this variant (Variation ID: 201607). This variant disrupts the C-terminus of the SDHB protein. Other variant(s) that disrupt this region (p.Ile263Serfs*13) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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