Submissions for variant NM_003000.3(SDHB):c.269G>A (p.Arg90Gln)

gnomAD frequency: 0.00004  dbSNP: rs570278423

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492424	SCV000581189	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-02	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 variant has been reported in several individuals with a paraganglioma (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. J Med Genet, 2015 Oct;52:647-56). At our laboratory, the variant has been detected in over 20 individuals; none of them reported to have a paraganglioma (Ambry internal data). This variant was also detected in an individual a gastrointestinal stromal tumor, which retained SDHB expression on immunostaining (Klinke OK et al. PLoS One, 2015 Jun;10:e0130149). One functional study demonstrated that the yeast equivalent of this variant moderately impairs succinate dehydrogenase function (Panizza E et al. Hum Mol Genet, 2013 Feb;22:804-15). 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 available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550029	SCV000630701	likely pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 90 of the SDHB protein (p.Arg90Gln). This variant is present in population databases (rs570278423, gnomAD 0.008%). This missense change has been observed in individuals with breast cancer and/or paraganglioma-pheochromocytoma syndromes (PMID: 17102082, 19351833, 20208144, 21520333, 26269449, 33558524, 34906457). ClinVar contains an entry for this variant (Variation ID: 201609). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 23175444). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778775	SCV002015105	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2021-10-28	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.269G>A (p.Arg90Gln) results in a conservative amino acid change located in the 2Fe-2S ferredoxin-type iron-sulfur binding domain (IPR001041) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251332 control chromosomes. c.269G>A has been reported in the literature in comprehensively genotyped cohorts of individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome and in at-least one individual with bilateral breast cancer example, Neumann_2009, Castellano_2006, Hermsen_2010, Curras-Freixes_2015, Bernardo-Castineira_2019, Moradian_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect as it has been shown to reduce but not entirely abolish SDHB enzymatic activity in a yeast experimental system (Panizza_2013). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4; likely pathogenic, n=1). Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
All of Us Research Program, National Institutes of Health	RCV001778775	SCV004832447	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 90 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional complementation studies in yeast have reported mildly impaired SDHB protein function (PMID: 23175444). This variant has been reported in individuals affected with hereditary paranganglioma-pheochromocytoma syndrome in the literature (PMID: 17102082, 19351833, 20208144, 26102504 , 26269449, 30549360, 31216007), but has also been reported in unaffected individuals (ClinVar Variation ID: VCV000201609, SCV000581189.5). This variant has been identified in 3/282738 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV004567383	SCV005056630	uncertain significance	Gastrointestinal stromal tumor	2024-02-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000782211	SCV005435824	uncertain significance	not provided	2024-09-01	criteria provided, single submitter	clinical testing	SDHB: PM5, PM2:Supporting, PS3:Supporting, PS4:Supporting
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.