Submissions for variant NM_003000.3(SDHB):c.423+20T>A

gnomAD frequency: 0.00179  dbSNP: rs190139590

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000183209	SCV000053117	benign	not specified	2017-06-22	criteria provided, single submitter	clinical testing	Variant summary: The SDHB c.423+20T>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and 4/5 splice prediction tools predict changes of a cryptic splicing site. ESEfinder predicts changes of RNA splicing enhancer sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 374/121320 control chromosomes (4 homozygotes) at a frequency of 0.0030828, which is approximately 3523 times the estimated maximal expected allele frequency of a pathogenic SDHB variant (0.0000009), suggesting this variant is likely a benign polymorphism. This variant has been reported in the affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
GeneDx	RCV000183209	SCV000235628	likely benign	not specified	2017-06-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204733	SCV000262420	benign	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000183209	SCV000309330	benign	not specified		criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000183209	SCV000540302	likely benign	not specified	2017-02-13	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been classified in HGMD as DM. It has been seen in 2 patients with pheochromocytomas and one with GIST. It is present with a MaxMAF of 0.89% in ExAC (high for disease frequency - 0.8/100,000 person-years). It is classified in ClinVar with 1 star as benign/likely benign by Invitae, GeneDx, Prevention genetics and as likely path by LabCorp (in 2011).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514661	SCV000610707	likely benign	not provided	2017-07-07	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755700	SCV000883133	uncertain significance	Paragangliomas 4	2018-11-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000986264	SCV001135203	likely benign	Gastrointestinal stromal tumor	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514661	SCV001158675	benign	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257364	SCV002527074	benign	Hereditary cancer-predisposing syndrome	2020-05-29	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000514661	SCV002543876	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	SDHB: BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000183209	SCV002552174	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002257364	SCV002632090	uncertain significance	Hereditary cancer-predisposing syndrome	2015-08-06	criteria provided, single submitter	clinical testing	The c.423+20T>A intronic variant results from a T to A substitution 20 nucleotides after coding exon 4 in the SDHB gene. In one study, this alteration was reported in 2 apparently unrelated individuals with an adrenal pheochromocytoma diagnosed prior to age 50 (Srirangalingam U et al. Clin Endocrinol. 2008 Oct;69(4):587-96). Neither of these probands had an identifiable VHL mutation; however, other susceptibility genes were not assessed. Authors classified c.423+20T>A as a mutation, but cautioned that further studies were needed to confirm pathogenicity. This variant was previously reported in the SNPDatabase as rs190139590. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.22% (28/13006), having been observed in 0.02% (1/4406) of African American alleles, and in 0.31% (27/8600) of European American alleles studied. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 0.05% (1/2184). The highest observed frequency was 1 of 178 (0.56%) British chromosomes studied. To date, this alteration has been detected with an allele frequency of approximately 0.03% (greater than 6100 alleles tested) in our clinical cohort. Based on nucleotide sequence alignment, this position is poorly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a cryptic splice acceptor site in close proximity to the native donor site; however, direct evidence is unavailable. Since supporting evidence for this variant is conflicting at this time, the clinical significance of c.423+20T>A remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000514661	SCV001550911	likely benign	not provided		no assertion criteria provided	clinical testing	The SDHB c.423+20T>A variant was identified in the in heterozygous state in the tumour of one patient with pheochromocytoma (Pantaleo_2014_23612575) and in the tumours of two patients with Carney Triad (association of paragangliomas, pulmonary chondromas, and gastrointestinal stromal tumors with variety of other lesions including pheochromocytomas and adrenocortical tumors) who were also found to have SDHD c.388insG variants (Szarek_2015_25808178). The variant was also identified in dbSNP (ID: rs190139590) as “With Likely pathogenic allele”. The variant was found in ClinVar with conflicting interpretations of pathogenicity as it was classified as likely benign by Children's Mercy Hospital and Clinics, GeneDx, and Laboratory for Molecular Medicine at Partners HealthCare Personalized Medicine, benign by Prevention Genetics and Invitae, but was classified as likely pathogenic by Integrated Genetics/Laboratory Corporation of America. The variant was found in LOVD 3.0 where it was reported as likely benign. The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 847 of 282734 chromosomes (8 homozygous) at a frequency of 0.002996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 295 of 30614 chromosomes (freq: 0.009636), Ashkenazi Jewish in 69 of 10370 chromosomes (freq: 0.006654), Other in 28 of 7224 chromosomes (freq: 0.003876), European (Non-Finnish) in 370 of 129148 chromosomes (freq: 0.002865), Latino in 71 of 35438 chromosomes (freq: 0.002003), European (Finnish) in 10 of 25020 chromosomes (freq: 0.0004), African in 3 of 24966 chromosomes (freq: 0.00012) and East African in 1 of 19954 chromosomes (freq: 0.00005). Pathogenic variants in SDHB have been associated with Cowden Syndrome, an autosomal dominant condition with an estimated prevalence of 1 in 200 000 and Paragangliomas, an autosomal dominant condition with an estimated prevalence of 1 in 1 000 000. The observed allele frequency is therefore higher than would be expected for the disorder. Three in silico splicing programs (SpliceSiteFinder-like, MaxEntScan, NNSPLICE) predict a greater than 10% change in splicing which would lead to the creation of a new 3' splice site, however MutationTaster predicts that this variant is a polymorphism. This information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Pantaleo, Maria A., et al. "Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST." European Journal of Human Genetics 22.1 (2014): 32. Szarek, Eva, et al. "Carney triad, SDH-deficient tumors, and Sdhb+/− mice share abnormal mitochondria." Endocrine-related cancer 22.3 (2015): 345-352.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000514661	SCV001808242	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000514661	SCV001926753	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000514661	SCV001952149	likely benign	not provided		no assertion criteria provided	clinical testing