ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.269G>A (p.Arg90Gln) (rs570278423)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492424 SCV000581189 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing The p.R90Q variant (also known as c.269G>A), located in coding exon 3 of the SDHB gene, results from a G to A substitution at nucleotide position 269. The arginine at codon 90 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in several individuals with head and neck PGL, including one individual with sporadic bilateral tympanic and carotid head and neck PGL diagnosed at age 33 (Castellano M et al. Ann. N. Y. Acad. Sci., 2006 Aug;1073:156-65; Neumann HP et al. Cancer Res., 2009 Apr;69:3650-6; Hermsen MA et al. Cell. Oncol., 2010 Jan;32:275-83; Currás-Freixes M et al, 2015 Oct;52:647-56). Yeast functional studies found that the analogous yeast strain (yR84Q) demonstrated decreased SDH activity, partial growth complementation, normal respiratory activity, mtDNA stability similar to wild type, and nuclear point mutability similar to null mutants; based on these results, the authors classified this alteration as having a mildly impaired phenotype (Panizza E et al. Hum. Mol. Genet., 2013 Feb;22:804-15). Structural analysis indicates that this alteration is located in a key, sensitive region and is likely to destabilize protein function (Ambry internal analysis). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000550029 SCV000630701 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-09-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 90 of the SDHB protein (p.Arg90Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs570278423, ExAC 0.01%). This variant has been reported in several individuals affected with head and neck paragangliomas in the literature (PMID: 26269449, 17102082, 20208144, 19351833) and in the Leiden Open-source Variation Database (PMID: 21520333). Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 201609). This missense change has been shown to reduce but not entirely abolish SDHB enzymatic activity (PMID: 23175444). In summary, this is a rare missense variant that may impact SDHB protein function and has been reported in several individuals affected with an SDHB-related cancer. However, in the absence of additional genetic or functional studies it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000782211 SCV001433593 uncertain significance not provided 2020-09-17 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function Published functional studies in yeast demonstrate reduced SDH activity (Panizza 2013) Observed in individuals with SDHB-related tumors (Castellano 2006, Neumann 2009, Hermsen 2010, Curras-Freixes 2015, Bernardo-Castineira 2019)
Gharavi Laboratory,Columbia University RCV000782211 SCV000920696 uncertain significance not provided 2018-09-16 no assertion criteria provided research
Center of Medical Genetics and Primary Health Care RCV001004837 SCV000987258 uncertain significance bilateral breast cancer 2020-07-22 no assertion criteria provided research ACMG Guidelines 2015 criteria This variant is in exon 3 of the SDHB gene in the Fer2_3 domain (F42-147Y aa); it is involved in electron transfer activity, iron-sulfur cluster binding. This missense change has been shown to reduce but not entirely abolish SDHB enzymatic activity (PMID: 23175444) (PS3 Pathogenic Very Strong). This variant has been reported as pathogenic in paraganglioma (Panizzaet al., 2013). This variant is in a hotspot of 10 pathogenic missense, nonsense, and frameshift variants (source ClinVar) (PM1 Pathogenic Moderate). There is a known pathogenic null (terminating) variant (i.e., c.268C>T (p.Arg90Ter) at the same amino acid residue which also suggests that this region is a mutational hotspot (PS1 Pathogenic Strong). The allele count in GnomAD exomes and GnomAD genomes are 2 and 1, respectively, which are less the threshold 5 for dominant gene SDHB (PM2 Pathogenic Moderate). 11 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT versus no benign predictions support its deleterious effect (PP3 Pathogenic Supporting). This variant is reported in ClinVar as a likely pathogenic variant or a VUS. In this study this variant was found in a 46-year-old female with bilateral breast cancer and no reported family history of cancer. Based on the evidence provided above, we classified this variant as a Variant of Unknown Significance.

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