ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.744C>G (p.Asn248Lys) (rs1131691058)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492396 SCV000581209 likely pathogenic Hereditary cancer-predisposing syndrome 2019-02-14 criteria provided, single submitter clinical testing The p.N248K variant (also known as c.744C>G), located in coding exon 7 of the SDHB gene, results from a C to G substitution at nucleotide position 744. The asparagine at codon 248 is replaced by lysine, an amino acid with similar properties. This alteration has been previously described in individuals with head and neck or pneumogastric paraganglioma (Persu A et al. J. Hypertens., 2008 Jul;26:1395-401; Papathomas TG et al. Mod. Pathol., 2015 Jun;28:807-21). Based on internal structural assessment, this variant introduces a positive charge near the quinone-reducing active site and affects the final electron transfer reaction (Sun F et al. Cell, 2005 Jul;121:1043-57; Liu J et al. Chem. Rev., 2014 Apr;114:4366-469). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001058694 SCV001223283 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-01-14 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 248 of the SDHB protein (p.Asn248Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with paraganglioma (PMID: 18551016). ClinVar contains an entry for this variant (Variation ID: 428929). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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