Submissions for variant NM_003000.3(SDHB):c.287-1G>C

dbSNP: rs397516833

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037719	SCV000061381	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2012-12-06	criteria provided, single submitter	clinical testing	The 287-1G>C variant in SDHB has been reported in one individual with paragangli oma and segregated with disease in one affected relative in that family (Timmers 2007). This variant has also been identified in a benign paraganglioma sample ( Klein 2008). This variant occurs in the invariant region (+/- 1,2) of the splic e consensus sequence and is predicted to cause altered splicing leading to an ab normal or absent protein. In summary, the 287-1G>C variant is likely pathogenic, though additional studies are required to fully establish its clinical signific ance.
Ambry Genetics	RCV000128907	SCV000172774	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-27	criteria provided, single submitter	clinical testing	The c.287-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 4 of the SDHB gene. This alteration has been reported in an individual with PGL-PCC and a positive family history (Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar;92:779-86). This alteration was also reported in three other patients with PGL-PCC (Klein RD et al. Diagn. Mol. Pathol. 2008 Jun;17:94-100; Jafri M et al. Clin. Endocrinol. (Oxf) 2013 Jun;78:898-906; Sue M et al. Eur. J. Endocrinol. 2015 Feb;172:89-95). A similar alteration (c.278-2A>G) has been reported in several families with PGL-PCC (Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Neumann HP et al. JAMA 2004 Aug;292:943-51). 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.
Eurofins Ntd Llc (ga)	RCV000478921	SCV000343112	pathogenic	not provided	2016-06-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000478921	SCV000565544	pathogenic	not provided	2017-11-16	criteria provided, single submitter	clinical testing	This variant is denoted SDHB c.287-1G>C or IVS3-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 3 of the SDHB gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in multiple cases with malignant paraganglioma, at least one of which showed absence of SDHB staining by immunohistochemistry (Timmers 2007, He 2009, Fishbein 2013, Jafri 2013, Sue 2015, Del Forno 2016, Gupta 2016, Jochmanova 2017). Based on currently available evidence, we consider SDHB c.287-1G>C to be a pathogenic variant.
Counsyl	RCV000332692	SCV000677729	pathogenic	Paragangliomas 4	2017-05-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633965	SCV000755238	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 of the SDHB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with paraganglioma-pheochromocytoma syndromes (PMID: 17200167, 18382370, 19454582, 27549546, 30050099, 34750850; internal data). This variant is also known as IVS3-1 G>C. ClinVar contains an entry for this variant (Variation ID: 44642). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037719	SCV001821468	pathogenic	Hereditary pheochromocytoma-paraganglioma	2021-08-08	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.287-1G>C 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 the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251204 control chromosomes. c.287-1G>C has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Timmers_2007, Jafri_2013, Fishbein_2013, Del Forno_2016, LaDuca_2017, Rinelli_2020). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000478921	SCV004123317	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	SDHB: PVS1, PM2
All of Us Research Program, National Institutes of Health	RCV000037719	SCV004831695	pathogenic	Hereditary pheochromocytoma-paraganglioma	2024-01-04	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. A different variant at the same splice site has been reported in association with disease and is independently classified as likely pathogenic or pathogenic. This variant has been reported in multiple individuals with paraganglioma (PMID: 17200167, 18382370, 23072324, 25371406, 36786389, 28179334, 27549546, 30050099, 28374168, 36387130). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Myriad Genetics, Inc.	RCV000332692	SCV005084499	pathogenic	Paragangliomas 4	2024-04-02	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 31883676, 32035780, 31492822, 35460558].
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000037719	SCV000599494	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research