Submissions for variant NM_003000.3(SDHB):c.136C>T (p.Arg46Ter)

gnomAD frequency: 0.00003  dbSNP: rs74315370

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132150	SCV000187222	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	clinical testing	The p.R46* pathogenic mutation (also known as c.136C>T), located in coding exon 2 of the SDHB gene, results from a C to T substitution at nucleotide position 136. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been reported multiple times as a disease-causing mutation in patients with PGL-PCC or renal cell carcinoma (Benn DE et al. Oncogene. 2003 Mar;22:1358-64; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36; Brouwers FM et al. J. Clin. Endocrinol. Metab. 2006 Nov;91:4505-9; Srirangalingam U et al. Clin. Endocrinol. 2008 Oct;69:587-96; Ricketts C et al. J. Natl. Cancer Inst. 2008 Sep;100:1260-2; Ghayee HK et al. Endocr. Relat. Cancer. 2009 Mar;16:291-9; Bayley JP et al. BMC Med. Genet. 2006 Jan;7:1; Mason EF et al. Am. J. Surg. Pathol. 2013 Oct;37:1612-8; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175(4):311-23; Chew WHW et al. Mol Genet Genomic Med. 2017 Sep;5(5):602-607). 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.
GeneDx	RCV000183224	SCV000235644	pathogenic	not provided	2021-10-22	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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20418362, 21348866, 27539324, 12618761, 18728283, 23797725, 16405730, 19075037, 18419787, 16912137, 18840642, 19454582, 16317055, 22517557, 17102084, 26916530, 28374168, 28204537, 28152038, 30050099, 30122763, 31851316, 29623478, 30694796, 32082649, 30871634, 31492822, 29625052, 32741965, 33087929, 30787465)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228450	SCV000287758	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg46*) 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 (rs74315370, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with pheochromocytoma, paraganglioma, and renal cell carcinoma (PMID: 12618761, 16405730, 18728283, 21348866, 23797725). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142763). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660253	SCV000782271	pathogenic	Paragangliomas 4	2016-11-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474784	SCV004202988	pathogenic	Gastrointestinal stromal tumor	2023-12-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000660253	SCV004362283	pathogenic	Paragangliomas 4	2023-05-01	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 2 of the SDHB gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with pheochromocytoma/paraganglioma (PMID: 19075037, 19454582, 21348866, 21909610, 23797725, 27539324, 28944243, 30122763). This variant has been identified in 5/282738 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHB function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000505277	SCV004821944	pathogenic	Hereditary pheochromocytoma-paraganglioma	2024-02-05	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 2 of the SDHB gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with pheochromocytoma/paraganglioma (PMID: 19075037, 19454582, 21348866, 21909610, 23797725, 27539324, 28944243, 30122763). This variant has been identified in 5/282738 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHB function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000505277	SCV004847568	pathogenic	Hereditary pheochromocytoma-paraganglioma	2020-08-10	criteria provided, single submitter	clinical testing	The p.Arg46X variant in SDHB has been reported in 11 individuals with SDHB-associated tumors and segregated with disease in 5 affected individuals from 3 families (Ricketts 2008 PMID:18728283, Srirangalingam 2008 PMID:18419787, Ghayee 2009 PMID:19075037, Hensen 2012 PMID:21348866, Mason 2013 PMID:23797725, Pandit 2016 PMID:27539324, Richter 2019 PMID:30050099). It has also been identified in 0.014% (1/7218) of "Other" or 0.008% of Finnish (2/25082) chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 142763). This nonsense variant leads to a premature termination codon at position 46, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SDHB gene is an established disease mechanism in autosomal dominant hereditary paraganglioma and pheochromocytoma. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary paraganglioma and pheochromocytoma. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting, PP1_Moderate
Myriad Genetics, Inc.	RCV000660253	SCV004933631	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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV004554715	SCV005043968	pathogenic	SDHB-related disorder	2024-03-28	criteria provided, single submitter	clinical testing	PVS1, PS4
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505277	SCV000599486	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research
Gharavi Laboratory, Columbia University	RCV000183224	SCV000920697	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research