Submissions for variant NM_003000.2(SDHB):c.136C>T (p.Arg46Ter) (rs74315370)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132150	SCV000187222	pathogenic	Hereditary cancer-predisposing syndrome	2018-10-09	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	2020-08-26	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 a significant frequency in large population cohorts (Lek 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)
Invitae	RCV000228450	SCV000287758	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2020-09-13	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. This variant is present in population databases (rs74315370, ExAC 0.02%). This variant has been observed in individuals affected with pheochromocytoma, paraganglioma, and renal cell carcinoma (PMID: 12618761, 16405730, 18728283, 21348866, 23797725). ClinVar contains an entry for this variant (Variation ID: 142763). Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). 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
Section on Medical Neuroendocrinolgy,National Institutes of Health	RCV000505277	SCV000599486	pathogenic	Hereditary Paraganglioma-Pheochromocytoma Syndromes		no assertion criteria provided	research
Gharavi Laboratory,Columbia University	RCV000183224	SCV000920697	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research