ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.72+1G>T (rs587782703)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132151 SCV000187223 pathogenic Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing The c.72+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the SDHB gene. This mutation has been detected in multiple PGL-PCC patients and families (Benn DE et al. J Clin Endocrinol Metab. 2006: 91(3); 827-836; Brouwers FM et al. J Endocrinol Metab. 2006;91(11):4505-9; Timmers HJ et al. J Clin Endocrinol Metab. 2007;92(3): 779-86; Tsang VH et al. Endocr Relat Cancer. 2014 May 6;21(3):415-26; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143(8):1421-1435). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000153923 SCV000203540 pathogenic not provided 2013-12-10 criteria provided, single submitter clinical testing
GeneDx RCV000153923 SCV000279239 pathogenic not provided 2021-04-15 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a 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 et al., 2016); This variant is associated with the following publications: (PMID: 16317055, 16912137, 16472267, 17667967, 18419787, 19864450, 20459544, 20418362, 23666964, 24623741, 29204718, 29386252, 32581362, 31492822, 30050099, 28748451, 29623478, 30694796, 29909963, 26556299, 27910947, 28374168, 28973655, 19522823, 26916530, 19215943, 21934479, 17200167, 25741136)
Invitae RCV000232241 SCV000287785 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-06-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the SDHB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with pheochromocytoma (PMID: 16317055, 23666964), paraganglioma (PMID: 16472267, 16912137, 18419787, 20418362), gastrointestinal stromal tumor (PMID: 17667967), and renal cell carcinoma (PMID: 20459544). This variant is also known as IVS1+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 142764). Experimental studies carried out using the blood and tumor RNA of an affected individual have shown that this splicing change results in an aberrant transcript predicted to result in a truncated protein product (PMID: 17667967). Two different variants affecting this nucleotide (c.72+1G>A and c.72+1G>C ) have been reported in individuals affected with paraganglioma and pheochromocytoma (PMID: 19454582, 19802898), indicating that this nucleotide may be crucial for normal mRNA splicing. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
Academic Department of Medical Genetics, University of Cambridge RCV000132151 SCV000992189 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001437 SCV001158674 pathogenic not specified 2019-06-10 criteria provided, single submitter clinical testing The SDHB c.72+1G>T variant (rs587782703) is reported in the literature in individuals affected with pheochromocytoma (Benn 2006, Timmers 2007, Tsang 2014), paraganglioma (Brouwers 2006), gastrointestinal tumor (Pasini 2008, McWhinney 2008), and renal cell carcinoma (Schrader 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 142764), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 1, which is likely to negatively impact gene function, and functional analyses of patient mRNA shows aberrant splicing (Pasini 2008). Additionally, other variants at this nucleotide (c.72+1G>A, c.72+1G>C) have been reported in individuals with pheochromocytoma or paraganglioma and are considered pathogenic (Burnichon 2009, Ricketts 2010). Based on available information, the c.72+1G>T variant is considered to be pathogenic. References: Benn DE et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36. Brouwers FM et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006 Nov;91(11):4505-9. Burnichon N et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27. McWhinney SR et al. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med. 2007 Sep 6;357(10):1054-6. Pasini B et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008 Jan;16(1):79-88. Ricketts CJ et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 2010 Jan;31(1):41-51. Schrader KA et al. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol. 2016 Jan;2(1):104-11. Timmers HJ et al. Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. J Clin Endocrinol Metab. 2007 Mar;92(3):779-86. Tsang VH et al. Overexpression of miR-210 is associated with SDH-related pheochromocytomas, paragangliomas, and gastrointestinal stromal tumours. Endocr Relat Cancer. 2014 May 6;21(3):415-26.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000505343 SCV001737432 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2021-06-10 criteria provided, single submitter clinical testing The SDHB c.72+1G>T intronic change results in a G to T substitution at the +1 position of intron 1 of the SDHB gene. This variant is predicted to result in loss of the native splice donor site and abnormal gene splicing, resulting in nonsense-mediated decay or an abnormal protein product (PVS1). This variant has a maximum subpopulation frequency of 0.0028% in gnomAD v2.1.1 (PM2_Supporting; This variant has been reported in individuals with pheochromocytoma (PMID: 16317055, 18419787, 23666964, 31492822), paraganglioma (PMID: 16472267, 16912137, 20418362, 29909963, 30050099), gastrointestinal stromal tumor (PMID: 17804857), and renal cell carcinoma (PMID: 20459544, 26556299). This variant is also known as IVS1+1G>T in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000505343 SCV001821404 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2021-08-27 criteria provided, single submitter clinical testing Variant summary: SDHB c.72+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5` splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and indicated that the first part of intron 1 was transcribed with the frameshift resulting in a stop codon in the middle of exon 2, predicting a truncated protein (Pasini_2007). The variant allele was found at a frequency of 1.2e-05 in 242838 control chromosomes (gnomAD). c.72+1G>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (Pasini_2007, Benn_2018, Richter_2019, Dwight_2021). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000013630 SCV000033877 pathogenic Carney-Stratakis syndrome 2008-01-01 no assertion criteria provided literature only
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505343 SCV000599479 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research

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