Submissions for variant NM_003000.3(SDHB):c.541-2A>G

dbSNP: rs786201161

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162804	SCV000213285	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	The c.541-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the SDHB gene. This mutation was detected in several individuals with personal and/or family history of pheochromocytoma, paraganglioma, and renal cell carcinoma (Ambry internal data; Timmers HJ et al. J Clin Endocrinol Metab. 2007;92(3):779-86. Ricketts CJ et al. J Urol. 2012 Dec;188(6):2063-71. Choat H, et al. Case Rep Endocrinol 2014 ; 2014:502734; Casey RT et al. J. Clin. Endocrinol. Metab., 2017 11;102:4013-4022; Huang Y et al. Endocr Connect, 2018 Dec;7:1217-1225). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as a disease-causing mutation.
Illumina Laboratory Services, Illumina	RCV000374774	SCV000351417	likely pathogenic	SDHB-related disorder	2016-06-14	criteria provided, single submitter	clinical testing	The c.541-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in three studies in which it is found in a total of four hereditary paraganglioma-pheochromocytoma syndrome patients, all in a heterozygous state (Timmers et al. 2007; Ricketts et al. 2012; Choat et al. 2014). The variant was absent from an unaffected brother of one of the patients (Choat et al. 2014). Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Based on the evidence and the potential impact of splice acceptor variants, the c.541-2A>G variant is classified as likely pathogenic for SDHB-related disorders.
GeneDx	RCV000523104	SCV000616872	pathogenic	not provided	2022-12-21	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of a critical region, including the 4FE-4S ferredoxin-type domain and Iron-sulfur 2 (4Fe-4S), Iron-sulfur 3 (3Fe-4S), and ubiquinone binding sites (UniProt); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23083876, 25525159, 25298897, 28748451, 25873086, 17200167, 28374168, 27159321, 28973655, 30352407, 19351833, 26642834, 29504908, 25371406, 31705439, 31579262, 32124427, 31492822, 27535533, 34703596)
Invitae	RCV000797086	SCV000936626	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 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 leukodystrophic encephalopathy and paragangliomas and pheochromocytomas (PMID: 17200167, 23083876, 25298897, 26642834). This variant is also known as IVS5–2A>G. ClinVar contains an entry for this variant (Variation ID: 183925). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505364	SCV002050812	pathogenic	Hereditary pheochromocytoma-paraganglioma	2021-12-07	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.541-2A>G 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 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249478 control chromosomes. c.541-2A>G has been reported in the literature in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome with reduced penetrance (e.g. Timmers_2007, Neumann_2009, Jochmanova_2017). Four 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003474848	SCV004203039	pathogenic	Gastrointestinal stromal tumor	2022-04-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004019954	SCV004933756	pathogenic	Paragangliomas 4	2024-02-08	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: 31705439, 25298897, 17538171, 29504908, 23083876].
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505364	SCV000599511	pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research