ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.784_787dup (p.Ile263fs) (rs1553176976)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485215 SCV000570627 likely pathogenic not provided 2017-03-27 criteria provided, single submitter clinical testing This duplication of four nucleotides in SDHB is denoted c.784_787dupGCTA at the cDNA level and p.Ile263SerfsX13 (I263SfsX13) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is GAAA[dupGCTA]TTGC. The duplication causes a frameshift which changes an Isoleucine to a Serine at codon 263, and creates a premature stop codon at position 13 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 18 amino acids are no longer translated correctly and is predicted to cause loss of normal protein function through protein truncation. Although this variant has not, to our knowledge, been reported in the literature, the disrupted region includes several residues that are conserved across species, and other nonsense or frameshift variants causing a similar impact have been reported in individuals with paraganglioma or pheochromocytoma (Neumann 2009, Rattenberry 2013, Pai 2015). Based on currently available information, we consider SDHB c.784_787dupGCTA to be a likely pathogenic variant.
Invitae RCV000696403 SCV000824964 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2018-05-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SDHB gene (p.Ile263Serfs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acids of the SDHB protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with paraganglioma or pheochromocytoma (Invitae). A different variant with a similar protein effect (p.Ile263Tyrfs*12) has also been observed in two individuals in a family that are affected with renal cell carcinoma (Invitae). ClinVar contains an entry for this variant (Variation ID: 421424). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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