ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.166_170del (p.Pro56fs)
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.166_170del (p.Pro56fs)
Variation ID: 185342 Accession: VCV000185342.35
- Type and length
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Deletion, 5 bp
- Location
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Cytogenetic: 1p36.13 1: 17044791-17044795 (GRCh38) [ NCBI UCSC ] 1: 17371286-17371290 (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 Oct 10, 2018 May 1, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.166_170del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Pro56fs frameshift NM_003000.2:c.166_170delCCTCA NC_000001.11:g.17044792_17044796del NC_000001.10:g.17371287_17371291del NG_012340.1:g.14376_14380del LRG_316:g.14376_14380del LRG_316t1:c.166_170del LRG_316p1:p.Pro56fs - Protein change
- P56fs
- Other names
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- Canonical SPDI
- NC_000001.11:17044790:TGAGGT:T
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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.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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 (1) |
criteria provided, single submitter
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Oct 26, 2022 | RCV000164746.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV000467539.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 21, 2019 | RCV001002472.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2022 | RCV001294007.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 22, 2023 | RCV001257497.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 7, 2023 | RCV001753560.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 10, 2022 | RCV002498816.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 28, 2022 | RCV003474863.1 |
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
Help
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
Help
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
(Dec 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Pheochromocytoma
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001482758.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 15328326, 21934479, 25130709, … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 15328326, 21934479, 25130709, 28152038] (less)
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Pathogenic
(Jan 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pheochromocytoma
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074521.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant summary: SDHB c.166_170delCCTCA (p.Pro56TyrfsX5) 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.166_170delCCTCA (p.Pro56TyrfsX5) 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. This variant is also known as c.32_36delCCTCA in HGVS and 300-4delCCTCA in the literature. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251378 control chromosomes (gnomAD). c.166_170delCCTCA has been reported in the literature in multiple individuals affected with Paraganglioma and/or Pheochromocytoma (examples: Neumann_2004, Cascon_2009, Burnichon_2009, Andrews_2018 and Benn_2018). These data indicate that the variant is associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 07, 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: SCV002005666.2
First in ClinVar: Nov 06, 2021 Last updated: Feb 18, 2023 |
Comment:
Frameshift 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)
Frameshift 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 in large population cohorts (gnomAD); Also known as Pro28TyrfsX5; This variant is associated with the following publications: (PMID: 17652212, 25130709, 28152038, 30050099, 31216007, 21934479, 15328326, 31431315, 31092265, 30262796, 18551016, 28973655, 20208144, 18382370, 31492822, 24436918, 28529006, 31589614, 19258401, 33900943, 34313605) (less)
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Pathogenic
(Nov 28, 2022)
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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: SCV004203031.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 26, 2022)
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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: SCV000215418.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The c.166_170delCCTCA pathogenic mutation, located in coding exon 2 of the SDHB gene, results from a deletion of 5 nucleotides at nucleotide positions 166 to … (more)
The c.166_170delCCTCA pathogenic mutation, located in coding exon 2 of the SDHB gene, results from a deletion of 5 nucleotides at nucleotide positions 166 to 170, causing a translational frameshift with a predicted alternate stop codon (p.P56Yfs*5). This well-described mutation has been identified in numerous individuals with various tumors across the SDHx spectrum, including pheochromocytoma, paraganglioma, gastrointestinal stromal tumor (GIST), and/or renal cell carcinoma (Neumann HP et al. JAMA 2004 Aug;292(8):943-51; Mora J et al. Pediatr. Blood Cancer 2006 Nov;47(6):785-9; Amar L et al. J. Clin. Endocrinol. Metab. 2007 Oct;92(10):3822-8; Persu A et al. J. Hypertens. 2008 Jul;26(7):1395-401; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Gill AJ et al. Am. J. Surg. Pathol. 2011 Oct;35(10):1578-85). Haplotype analysis suggests that the c.166_170delCCTCA alteration is enriched in the Spanish population due to a founder effect (Cascón A et al. J. Clin. Endocrinol. Metab. 2009 May;94(5):1701-5). This alteration was originally described as c.300-4delCCTCA in the literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
(Mar 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160420.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The SDHB c.166_170delCCTCA; p.Pro56fs variant (rs786202100), also published as 300_304delCCTCA, is reported in the literature in numerous individuals affected with paraganglioma and/or pheochromocytoma (Amar 2007, … (more)
The SDHB c.166_170delCCTCA; p.Pro56fs variant (rs786202100), also published as 300_304delCCTCA, is reported in the literature in numerous individuals affected with paraganglioma and/or pheochromocytoma (Amar 2007, Burnichon 2009, Cascon 2009, Gill 2011, Jove 2014, Mora 2006, Neumann 2004). This variant has been discussed as a founder mutation in affected individuals of Spanish descent (Cascon 2009). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by several laboratories in ClinVar (Variation ID: 185342). This variant causes a frameshift by deleting five nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Amar L et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007 Oct;92(10):3822-8. Burnichon N et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27. Cascon A et al. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab. 2009 May;94(5):1701-5. Gill AJ et al. Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol. 2011 Oct;35(10):1578-85. Jove et al. Simultaneous KIT mutation and succinate dehydrogenase (SDH) deficiency in a patient with a gastrointestinal stromal tumour and Carney-Stratakis syndrome: a case report. Histopathology. 2014 Nov;65(5):712-7. Mora J et al. Pediatric paraganglioma: an early manifestation of an adult disease secondary to germline mutations. Pediatr Blood Cancer. 2006 Nov;47(6):785-9. Neumann HP et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. (less)
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Pathogenic
(Oct 29, 2019)
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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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Division of Medical Genetics, University of Washington
Study: CSER_CHARM
Accession: SCV001434314.1 First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
Comment:
This variant has been reported in the literature in multiple individuals affected with pheochromocytoma and/or paraganglioma [Neumann 2004, Mora 2006, Amar 2007, Cascon 2009, Gill … (more)
This variant has been reported in the literature in multiple individuals affected with pheochromocytoma and/or paraganglioma [Neumann 2004, Mora 2006, Amar 2007, Cascon 2009, Gill 2011, Jove 2014]. This variant leads to a translational frameshift and the introduction of a premature termination codon 5 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of SDHB is a well-established mechanism of disease for hereditary paraganglioma-pheochromocytoma syndrome [Burnichon 2009, Ricketts 2010]. This variant is not present in population databases (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PM2; PVS1 (less)
Indication for testing: Family history of colon cancer
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Pathogenic
(Apr 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
Pheochromocytoma Gastrointestinal stromal tumor Carney-Stratakis syndrome Mitochondrial complex 2 deficiency, nuclear type 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002806235.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018406.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Jan 28, 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: SCV000553997.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Pro56Tyrfs*5) 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.Pro56Tyrfs*5) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with pheochromocytoma and/or paraganglioma (PMID: 15328326, 16304664, 17652212, 19258401, 21934479, 25130709). This variant is also known as 300-4delCCTCA or c.300_304delCCTCA. ClinVar contains an entry for this variant (Variation ID: 185342). For these reasons, this variant has been classified as Pathogenic. (less)
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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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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 |
Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. | LaDuca H | PloS one | 2017 | PMID: 28152038 |
Simultaneous KIT mutation and succinate dehydrogenase (SDH) deficiency in a patient with a gastrointestinal stromal tumour and Carney-Stratakis syndrome: a case report. | Jové M | Histopathology | 2014 | PMID: 25130709 |
Renal tumors associated with germline SDHB mutation show distinctive morphology. | Gill AJ | The American journal of surgical pathology | 2011 | PMID: 21934479 |
Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management. | Hermsen MA | Cellular oncology : the official journal of the International Society for Cellular Oncology | 2010 | PMID: 20208144 |
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 |
Genetics of pheochromocytoma and paraganglioma in Spanish patients. | Cascón A | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19258401 |
High prevalence of SDHB mutations in head and neck paraganglioma in Belgium. | Persu A | Journal of hypertension | 2008 | PMID: 18551016 |
Germline SDHB mutations are common in patients with apparently sporadic sympathetic paragangliomas. | Klein RD | Diagnostic molecular pathology : the American journal of surgical pathology, part B | 2008 | PMID: 18382370 |
Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. | Amar L | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17652212 |
Pediatric paraganglioma: an early manifestation of an adult disease secondary to germline mutations. | Mora J | Pediatric blood & cancer | 2006 | PMID: 16304664 |
Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. | Neumann HP | JAMA | 2004 | PMID: 15328326 |
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Text-mined citations for rs786202100 ...
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.