ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.683_684del (p.Glu228fs) (rs762812025)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000798175 SCV000937776 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-11-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SDHB gene (p.Glu228Glyfs*27). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acids of the SDHB protein. This variant is present in population databases (rs762812025, ExAC 0.002%). This variant has been observed in several individuals affected with malignant paraganglioma (PMID: 24694336,16912137). ClinVar contains an entry for this variant (Variation ID: 438428). Different truncations (p.Ser239Tyrfs*8, deletion of exon 8) that lie downstream of this variant has been determined to be pathogenic (PMID: 15328326, Invitae). This suggests that deletion of this region of the SDHB protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001025703 SCV001187946 pathogenic Hereditary cancer-predisposing syndrome 2019-03-09 criteria provided, single submitter clinical testing The c.683_684delAG pathogenic mutation, located in coding exon 7 of the SDHB gene, results from a deletion of two nucleotides at nucleotide positions 683 to 684, causing a translational frameshift with a predicted alternate stop codon (p.E228Gfs*27). This alteration has been seen in multiple patients with paragangliomas (Brouwers FM et al. J. Clin. Endocrinol. Metab. 2006 Nov;91:4505-9; Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar;92:779-86; Welander J et al. J. Clin. Endocrinol. Metab. 2014 Jul;99:E1352-60; Sue M et al. Eur. J. Endocrinol. 2015 Feb;172:89-95; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435). 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.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505318 SCV000599527 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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