ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.423+20T>A (rs190139590)

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Total submissions: 11
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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.
Invitae RCV000204733 SCV000262420 benign Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2016-03-19 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000183209 SCV000309330 benign not specified criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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 RCV000183209 SCV001158675 benign not specified 2019-02-06 criteria provided, single submitter clinical testing
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

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