rs786201063
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000375499.8(SDHB):c.286+1G>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
SDHB
ENST00000375499.8 splice_donor
ENST00000375499.8 splice_donor
Scores
3
3
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.92
Genes affected
SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-17033059-C-T is Pathogenic according to our data. Variant chr1-17033059-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 183757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17033059-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.286+1G>A | splice_donor_variant | ENST00000375499.8 | NP_002991.2 | |||
SDHB | NM_001407361.1 | c.286+1G>A | splice_donor_variant | NP_001394290.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.286+1G>A | splice_donor_variant | 1 | NM_003000.3 | ENSP00000364649 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Paragangliomas 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 25, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 08, 2024 | 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: 30201732, 33391357, 17538171, 27539324]. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 09, 2024 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19802898, 25525159, 17308434, 16912137, 27539324, 26960314, 28374168, 22517557, 25683602, 17200167, 28152038, 19454582, 29623478, 17102085, 31492822, 34439371) - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 13, 2021 | The SDHB c.286+1G>A variant (rs786201063), also known as IVS3+1G>A, is reported in the literature in multiple individuals affected with paragangliomas and pheochromocytomas (Brouwers 2006, Isobe 2007, Pandit 2016, Timmers 2007). This variant is reported in ClinVar (Variation ID: 183757). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron three, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: 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. PMID: 16912137. Isobe K et al. Novel germline mutations in the SDHB and SDHD genes in Japanese pheochromocytomas. Horm Res. 2007;68(2):68-71. PMID: 17308434. Pandit R et al. Germline mutations and genotype-phenotype correlation in Asian Indian patients with pheochromocytoma and paraganglioma. Eur J Endocrinol. 2016 Oct;175(4):311-23. PMID: 27539324. 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. PMID: 17200167. - |
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change affects a donor 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 (PMID: 16912137, 17308434, 27539324). This variant is also known as IVS3+1 G>A. ClinVar contains an entry for this variant (Variation ID: 183757). 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. - |
Gastrointestinal stromal tumor Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 18, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2019 | The c.286+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the SDHB gene. This pathogenic variant has been reported in multiple unrelated individuals diagnosed with paragangliomas/pheochromocytomas (Brouwers FM et al. J. Clin. Endocrinol. Metab. 2006 Nov;91:4505-9; Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar;92:779-86; Isobe K et al. Horm. Res. 2007 Feb;68:68-71; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23). 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 a disease-causing mutation. - |
Hereditary pheochromocytoma-paraganglioma Pathogenic:1
Pathogenic, no assertion criteria provided | research | Section on Medical Neuroendocrinolgy, National Institutes of Health | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at