Submissions for variant NM_003000.3(SDHB):c.343C>T (p.Arg115Ter)

gnomAD frequency: 0.00001  dbSNP: rs751000085

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178185	SCV000230200	pathogenic	not provided	2015-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627752	SCV000644757	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg115*) in the SDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is present in population databases (rs751000085, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with paraganglioma and/or pheochromocytoma (PMID: 16405730, 21348866, 24523625, 25047027, 28490599). ClinVar contains an entry for this variant (Variation ID: 197210). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000505340	SCV000711787	pathogenic	Hereditary pheochromocytoma-paraganglioma	2016-06-22	criteria provided, single submitter	clinical testing	The p.Arg115X variant in SDHB has been reported in at least two individuals with hereditary paragangliomas and pheochromocytomas and segregated with disease in 1 affected relative (Bayley 2006, Benn 2006, Lefebvre 2006). It has also been id entified in 2/66740 European chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs751000085). This frequency is low en ough to be consistent with the frequency of hereditary paragangliomas and pheoch romocytomas in the general population. This nonsense variant is predicted to res ult in a premature termination codon at position 115, leading to a truncated or absent protein. Heterozygous loss-of-function variants in the SDHB gene are asso ciated with hereditary paragangliomas and pheochromocytomas. In summary, this va riant meets our criteria to be classified as pathogenic for hereditary paragangl iomas and pheochromocytomas in an autosomal dominant manner based on the predict ed impact to the protein and low frequency in controls.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505340	SCV001623275	pathogenic	Hereditary pheochromocytoma-paraganglioma	2021-05-11	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.343C>T (p.Arg115X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 251464 control chromosomes (gnomAD). c.343C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (e.g. Bayley_2006, Benn_2006, Timmers_2007, Guan_2015, Richter_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV001507023	SCV001711958	pathogenic	Paragangliomas 4	2021-05-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000178185	SCV001784301	pathogenic	not provided	2023-08-09	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24523625, 17200167, 25525159, 16317055, 25873086, 28503760, 21348866, 25683602, 28490599, 30352407, 31666924, 31447099, 32741965, 16405730, 35668420, 30050099, 32688340)
Ambry Genetics	RCV002453635	SCV002616919	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-13	criteria provided, single submitter	clinical testing	The p.R115* pathogenic mutation (also known as c.343C>T), located in coding exon 4 of the SDHB gene, results from a C to T substitution at nucleotide position 343. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in multiple patients with a personal history of paraganglioma and/or pheochromocytoma (Ambry internal data; Bayley JP et al. BMC Med. Genet., 2006 Jan;7:1; van Hulsteijn LT et al. Fam. Cancer, 2014 Dec;13:651-7; Martucci VL et al. Urol. Oncol., 2015 Apr;33:167.e13-20; Janssen I et al. Clin. Cancer Res., 2015 Sep;21:3888-95; Jochmanova I et al. J. Cancer Res. Clin. Oncol., 2017 Aug;143:1421-1435; Niemeijer ND et al. Eur. J. Endocrinol., 2017 Aug;177:115-125; Andrews KA et al. J. Med. Genet., 2018 06;55:384-394; Benn DE et al. J. Med. Genet., 2018 11;55:729-734; Huang Y et al. Endocr Connect, 2018 Dec;7:1217-1225; Richter S et al. Genet. Med., 2019 03;21:705-717). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003474933	SCV004203026	pathogenic	Gastrointestinal stromal tumor	2023-02-19	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000178185	SCV005198196	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000505340	SCV005424064	pathogenic	Hereditary pheochromocytoma-paraganglioma	2024-08-07	criteria provided, single submitter	clinical testing	The c.343C>T (p.Arg115*) variant in the SDHB gene is located on the exon 4 and introduces a premature translation termination codon (p.Arg115*), resulting in an absent or disrupted protein product. The variant has been reported in multiple unrelated individuals with paragangliomas/pheochromocytoma (PMID: 30352407, 28490599, 31666924, 29386252, 32688340). Loss-of-function variants of SDHB are known to be pathogenic (PMID: 16258955, 19389109, 28490599). The variant is reported in ClinVar (ID: 197210). The variant is rare in general population according to gnomAD (2/251464). Therefore, the c.343C>T (p.Arg115*) variant of SDHB has been classified as pathogenic.
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505340	SCV000599499	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000178185	SCV001927548	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000178185	SCV001957643	pathogenic	not provided		no assertion criteria provided	clinical testing