Submissions for variant NM_003000.3(SDHB):c.79C>T (p.Arg27Ter)

gnomAD frequency: 0.00003  dbSNP: rs74315369

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129929	SCV000184747	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	The p.R27* pathogenic mutation (also known as c.79C>T), located in coding exon 2 of the SDHB gene, results from a C to T substitution at nucleotide position 79. This changes the amino acid from an arginine to a stop codon within coding exon 2. The predicted stop codon occurs within the first 150 nucleotides of SDHB gene. This alteration may escape nonsense-mediated mRNAdecay and/or be rescued by re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653), and it impacts the first 57 amino acids of the protein. However, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This mutation has previously been reported in multiple cases of both sporadic and familial PGL-PCC as well as renal cell carcinoma (Cascón A et al. J. Med. Genet., 2002 Oct;39:E64; Vanharanta S et al. Am. J. Hum. Genet., 2004 Jan;74:153-9; Neumann HP et al. JAMA, 2004 Aug;292:943-51; Naito M et al. Endocrine, 2009 Aug;36:10-5; Graham D et al. Case Rep Genet, 2014 Aug;2014:273423; Casey RT et al. J. Clin. Endocrinol. Metab., 2017 11;102:4013-4022; Fife K et al. BMJ Case Rep, 2017 Aug;2017; Benn DE et al. J. Med. Genet., 2018 11;55:729-734; Albattal S et al. Oncotarget, 2019 Oct;10:5919-5931). Functional studies of this alteration have demonstrated the absence of SDH enzymatic activity as well as the absence of SDHB protein in cell-based assays, indicating nonsense-mediated mRNA decay or protein degradation as a mechanism for absent enzymatic activity (Kim E et al. Endocr. Relat. Cancer, 2015 Jun;22:387-97). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471400	SCV000554026	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2023-07-26	criteria provided, single submitter	clinical testing	This variant is also known as C213T. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 12783). This premature translational stop signal has been observed in individual(s) with pheochromocytoma (PMID: 12000816, 12362046, 14685938, 18382370, 19415531, 25215250). This variant is present in population databases (rs74315369, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Arg27*) 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).
GeneDx	RCV000657585	SCV000779322	pathogenic	not provided	2024-01-30	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; Observed in individuals with SDHB-related tumors (PMID: 12362046, 15328326, 18382370, 19415531, 23902947, 25215250, 28374168); Published functional studies demonstrate a damaging effect: absent SDHB protein production, absent SHD enzymatic activity, and abolished association with SDHA (PMID: 25972245); Not observed at significant frequency in large population cohorts (gnomAD); Also known as SDHB 213C>T; This variant is associated with the following publications: (PMID: 31579262, 31666924, 34439168, 29625052, 12000816, 19184535, 26916530, 12362046, 14685938, 15476441, 15328326, 18728280, 17102084, 12213855, 22517557, 25215250, 23902947, 19343621, 19415531, 18382370, 28374168, 30694796, 31492822, 31447099, 30787465, 30201732, 19802898, 27159321, 28784873, 36451132, 25972245)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000013623	SCV000840069	pathogenic	Paragangliomas 4	2018-02-06	criteria provided, single submitter	clinical testing	This c.79C>T (p.R27*) variant is predicted to result in a premature stop codon and has been reported in individuals with pheochromocytoma, paraganglioma and early-onset renal cell cancer (PMID: 12000816, 25215250, 18382370, 14685938, 14685938). In addition, in vitro studies have shown that the c.79C>T (p.R27*) variant alters SDHB expression and function. Therefore we classify this variant as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000013623	SCV002512413	pathogenic	Paragangliomas 4	2021-09-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505368	SCV004029458	pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-07-19	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.79C>T (p.Arg27X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250516 control chromosomes. c.79C>T has been reported in the literature in related individuals affected with Cardiac Paraganglioma, Renal cancer and Lung cancer (Example: Vanharanta_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 14685938). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003473085	SCV004202997	pathogenic	Gastrointestinal stromal tumor	2023-08-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000013623	SCV004933706	pathogenic	Paragangliomas 4	2024-02-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
OMIM	RCV000013623	SCV000033870	pathogenic	Paragangliomas 4	2002-05-09	no assertion criteria provided	literature only
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505368	SCV000599488	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research