ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.49A>G (p.Thr17Ala) (rs1060503756)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468636 SCV000553994 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 17 of the SDHB protein (p.Thr17Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with pheochromocytoma (PMID: 26269449, 30050099) or malignant paraganglioma (PMID: 22293219), as well as in individuals referred for genetic testing for pheochromocytoma and/or paraganglioma (PMID: 29386252). ClinVar contains an entry for this variant (Variation ID: 412461). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0). The alanine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this intronic variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001023387 SCV001185255 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-12 criteria provided, single submitter clinical testing The p.T17A variant (also known as c.49A>G), located in coding exon 1 of the SDHB gene, results from an A to G substitution at nucleotide position 49. The threonine at codon 17 is replaced by alanine, an amino acid with similar properties. This variant has been detected in a Portuguese individual with carotid body paraganglioma (Domingues R et al. J. Endocrinol. Invest. 2012 Dec;35:975-80) and in an individual with pheochromocytoma (Richter S et al. Genet. Med., 2019 03;21:705-717). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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