ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.343C>T (p.Arg115Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003000.3(SDHB):c.343C>T (p.Arg115Ter)
Variation ID: 197210 Accession: VCV000197210.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17028680 (GRCh38) [ NCBI UCSC ] 1: 17355175 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 28, 2015 May 1, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.343C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Arg115Ter nonsense NC_000001.11:g.17028680G>A NC_000001.10:g.17355175G>A NG_012340.1:g.30491C>T LRG_316:g.30491C>T LRG_316t1:c.343C>T LRG_316p1:p.Arg115Ter - Protein change
- R115*
- Other names
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- Canonical SPDI
- NC_000001.11:17028679:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SDHB | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1292 | 1407 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 9, 2023 | RCV000178185.13 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 11, 2021 | RCV000505340.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV000627752.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 7, 2020 | RCV002453635.3 | |
Pathogenic (1) |
criteria provided, single submitter
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May 23, 2021 | RCV001507023.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 19, 2023 | RCV003474933.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 04, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000230200.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jun 22, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711787.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Arg115X variant in SDHB has been reported in at least two individuals with hereditary paragangliomas and pheochromocytomas and segregated with disease in 1 affected … (more)
The p.Arg115X variant in SDHB has been reported in at least two individuals with hereditary paragangliomas and pheochromocytomas and segregated with disease in 1 affected relative (Bayley 2006, Benn 2006, Lefebvre 2006). It has also been id entified in 2/66740 European chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs751000085). This frequency is low en ough to be consistent with the frequency of hereditary paragangliomas and pheoch romocytomas in the general population. This nonsense variant is predicted to res ult in a premature termination codon at position 115, leading to a truncated or absent protein. Heterozygous loss-of-function variants in the SDHB gene are asso ciated with hereditary paragangliomas and pheochromocytomas. In summary, this va riant meets our criteria to be classified as pathogenic for hereditary paragangl iomas and pheochromocytomas in an autosomal dominant manner based on the predict ed impact to the protein and low frequency in controls. (less)
Number of individuals with the variant: 3
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Pathogenic
(May 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001623275.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
Variant summary: SDHB c.343C>T (p.Arg115X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: SDHB c.343C>T (p.Arg115X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 251464 control chromosomes (gnomAD). c.343C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (e.g. Bayley_2006, Benn_2006, Timmers_2007, Guan_2015, Richter_2019). 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. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001784301.4
First in ClinVar: Aug 14, 2021 Last updated: Aug 18, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24523625, 17200167, 25525159, 16317055, 25873086, 28503760, 21348866, 25683602, 28490599, 30352407, 31666924, 31447099, 32741965, 16405730, 35668420, 30050099, 32688340) (less)
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Pathogenic
(Feb 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Gastrointestinal stromal tumor
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004203026.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Gastrointestinal stromal tumor
Paragangliomas 4 Pheochromocytoma
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000644757.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg115*) in the SDHB gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg115*) in the SDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is present in population databases (rs751000085, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with paraganglioma and/or pheochromocytoma (PMID: 16405730, 21348866, 24523625, 25047027, 28490599). ClinVar contains an entry for this variant (Variation ID: 197210). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002616919.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R115* pathogenic mutation (also known as c.343C>T), located in coding exon 4 of the SDHB gene, results from a C to T substitution at … (more)
The p.R115* pathogenic mutation (also known as c.343C>T), located in coding exon 4 of the SDHB gene, results from a C to T substitution at nucleotide position 343. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in multiple patients with a personal history of paraganglioma and/or pheochromocytoma (Bayley JP et al. BMC Med. Genet., 2006 Jan;7:1; van Hulsteijn LT et al. Fam. Cancer, 2014 Dec;13:651-7; Martucci VL et al. Urol. Oncol., 2015 Apr;33:167.e13-20; Janssen I et al. Clin. Cancer Res., 2015 Sep;21:3888-95; Jochmanova I et al. J. Cancer Res. Clin. Oncol., 2017 Aug;143:1421-1435; Niemeijer ND et al. Eur. J. Endocrinol., 2017 Aug;177:115-125; Andrews KA et al. J. Med. Genet., 2018 06;55:384-394; Benn DE et al. J. Med. Genet., 2018 11;55:729-734; Huang Y et al. Endocr Connect, 2018 Dec;7:1217-1225; Richter S et al. Genet. Med., 2019 03;21:705-717). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(May 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001711958.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Hereditary pheochromocytoma-paraganglioma
Affected status: yes
Allele origin:
germline
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Section on Medical Neuroendocrinolgy, National Institutes of Health
Accession: SCV000599499.1
First in ClinVar: Sep 15, 2017 Last updated: Sep 15, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957643.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927548.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. | Richter S | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30050099 |
Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients. | Huang Y | Endocrine connections | 2018 | PMID: 30352407 |
Bayesian approach to determining penetrance of pathogenic SDH variants. | Benn DE | Journal of medical genetics | 2018 | PMID: 30201732 |
Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. | Andrews KA | Journal of medical genetics | 2018 | PMID: 29386252 |
The phenotype of SDHB germline mutation carriers: a nationwide study. | Niemeijer ND | European journal of endocrinology | 2017 | PMID: 28490599 |
SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations. | Jochmanova I | Journal of cancer research and clinical oncology | 2017 | PMID: 28374168 |
Superiority of [68Ga]-DOTATATE PET/CT to Other Functional Imaging Modalities in the Localization of SDHB-Associated Metastatic Pheochromocytoma and Paraganglioma. | Janssen I | Clinical cancer research : an official journal of the American Association for Cancer Research | 2015 | PMID: 25873086 |
Association of urinary bladder paragangliomas with germline mutations in the SDHB and VHL genes. | Martucci VL | Urologic oncology | 2015 | PMID: 25683602 |
Detection of inherited mutations for hereditary cancer using target enrichment and next generation sequencing. | Guan Y | Familial cancer | 2015 | PMID: 25151137 |
Phenotype of SDHB mutation carriers in the Netherlands. | van Hulsteijn LT | Familial cancer | 2014 | PMID: 25047027 |
Pheochromocytoma and paraganglioma syndromes: genetics and management update. | Lefebvre M | Current oncology (Toronto, Ont.) | 2014 | PMID: 24523625 |
High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. | Hensen EF | Clinical genetics | 2012 | PMID: 21348866 |
Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. | Ricketts CJ | Human mutation | 2010 | PMID: 19802898 |
The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. | Burnichon N | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19454582 |
Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. | Timmers HJ | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17200167 |
Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma. | Bayley JP | BMC medical genetics | 2006 | PMID: 16405730 |
Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. | Benn DE | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16317055 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SDHB | - | - | - | - |
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Text-mined citations for rs751000085 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.