ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.600G>T (p.Trp200Cys)
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.600G>T (p.Trp200Cys)
Variation ID: 183747 Accession: VCV000183747.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17024015 (GRCh38) [ NCBI UCSC ] 1: 17350510 (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 Sep 15, 2017 Feb 28, 2024 Nov 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.600G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Trp200Cys missense NC_000001.11:g.17024015C>A NC_000001.10:g.17350510C>A NG_012340.1:g.35156G>T LRG_316:g.35156G>T LRG_316t1:c.600G>T LRG_316p1:p.Trp200Cys - Protein change
- W200C
- Other names
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- Canonical SPDI
- NC_000001.11:17024014:C: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
Help
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 |
1253 | 1370 |
Conditions - Germline
Condition
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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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Apr 1, 2022 | RCV000162460.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2023 | RCV000462889.11 | |
Pathogenic (2) |
criteria provided, single submitter
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Mar 13, 2021 | RCV000505334.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 15, 2020 | RCV001523819.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2023 | RCV001577788.8 | |
Pathogenic (1) |
criteria provided, single submitter
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May 16, 2023 | RCV003474841.1 |
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
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 15, 2020)
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criteria provided, single submitter
Method: research
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Paragangliomas 4
Affected status: no
Allele origin:
germline
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Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Accession: SCV001478181.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
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Pathogenic
(Mar 13, 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: SCV001519621.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
Variant summary: SDHB c.600G>T (p.Trp200Cys) results in a non-conservative amino acid change located in the 4E-4S ferredoxin type, iron-sulfur binding domain (IPR017896) of the encoded … (more)
Variant summary: SDHB c.600G>T (p.Trp200Cys) results in a non-conservative amino acid change located in the 4E-4S ferredoxin type, iron-sulfur binding domain (IPR017896) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251310 control chromosomes. c.600G>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Drucker_2006, Timmers_2007, Klein_2008, Ricketts_2010, Alrashdi_2010, Greenberg_2020) and in at-least one report of an individual with gastrointestinal stromal tumor (GIST) who lacked mutations in KIT or PDGFRA (example, Janeway_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a dramatically reduced half-life reflective of increased protein degradation (example, Yang_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 01, 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: SCV000212817.7
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The p.W200C pathogenic mutation (also known as c.600G>T), located in coding exon 6 of the SDHB gene, results from a G to T substitution at … (more)
The p.W200C pathogenic mutation (also known as c.600G>T), located in coding exon 6 of the SDHB gene, results from a G to T substitution at nucleotide position 600. The tryptophan at codon 200 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been detected in multiple individuals with paragangliomas (PGL), pheochromocytomas (PCC), gastrointestinal stromal tumors (GIST), other tumors associated with hereditary PGL-PCC syndrome, and has also been implicated in Carney triad (Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar;92(3):779-786; Lodish MB et al. Endocr. Relat. Cancer. 2010 Sep;17(3):581-8; Drucker AM and Houlden RL. Nature Clin. Pract. Endocrinol. & Metab. 2006 Dec;2(12):702-6; Henderson A et al. Fam. Cancer 2009 Jan;8(3):257-60; Alrashdi I et al. Fam Cancer 2010 Sep;9(3):443-447; Janeway KA et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Jan;108(1):314-8; Andrews KA et al. J. Med. Genet. 2018 Jan; Boikos SA et al. Eur. J. Hum. Genet. 2016 Apr;24(4):569-73). In addition to the clinical data presented in the literature, functional studies demonstrated rapid and significant loss of W200C mutant SDHB protein compared to wildtype in a protein stability cell based assay (Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 30, 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: SCV001805236.3
First in ClinVar: Aug 21, 2021 Last updated: Nov 11, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: results in an unstable protein and impairs binding with SDHAF1 (Yang et al., 2012; Maio et al., 2016); … (more)
Published functional studies demonstrate a damaging effect: results in an unstable protein and impairs binding with SDHAF1 (Yang et al., 2012; Maio et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17200167, 27812541, 18840642, 19286091, 18382370, 20418362, 20119652, 28374168, 19184535, 26173966, 25371406, 21173220, 19802898, 25394176, 27011036, 23282968, 17143317, 27006389, 26749241, 29386252, 28152038, 30949620, 32741965, 33087929, 34906457, 34308366, 35668420, 34703596, 28873162, 32062700, 35060925, 35441217, 34095481, Rutkowski2022[article], 22835832) (less)
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Pathogenic
(May 16, 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: SCV004203018.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV004230023.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been … (more)
The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with paraganglioma-pheochromocytoma syndrome. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 22835832) (less)
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Pathogenic
(Nov 24, 2023)
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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: SCV000554005.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 200 of the SDHB … (more)
This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 200 of the SDHB protein (p.Trp200Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paragangliomas (PMID: 17143317, 17200167, 18382370, 19184535, 19802898, 20119652, 21173220). ClinVar contains an entry for this variant (Variation ID: 183747). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832). For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV000599516.1
First in ClinVar: Sep 15, 2017 Last updated: Sep 15, 2017 |
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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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Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases. | Yngvadottir B | Human molecular genetics | 2022 | PMID: 35441217 |
Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD. | Garrett A | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906457 |
Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors. | Fiala EM | Nature cancer | 2021 | PMID: 34308366 |
KIT Mutation in Gastric Gastrointestinal Stromal Tumor in a Patient With Familial Paraganglioma Syndrome Type 4. | Houlden RL | AACE clinical case reports | 2021 | PMID: 34095481 |
Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome. | Greenberg SE | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32741965 |
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 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. | Boikos SA | JAMA oncology | 2016 | PMID: 27011036 |
Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB. | Maio N | Cell metabolism | 2016 | PMID: 26749241 |
Carney triad can be (rarely) associated with germline succinate dehydrogenase defects. | Boikos SA | European journal of human genetics : EJHG | 2016 | PMID: 26173966 |
Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. | Miettinen M | The American journal of surgical pathology | 2013 | PMID: 23282968 |
Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function. | Yang C | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2012 | PMID: 22835832 |
Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. | Janeway KA | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 21173220 |
Succinate dehydrogenase gene mutations are strongly associated with paraganglioma of the organ of Zuckerkandl. | Lodish MB | Endocrine-related cancer | 2010 | PMID: 20418362 |
Carney triad versus Carney Stratakis syndrome: two cases which illustrate the difficulty in distinguishing between these conditions in individual patients. | Alrashdi I | Familial cancer | 2010 | PMID: 20119652 |
Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. | Ricketts CJ | Human mutation | 2010 | PMID: 19802898 |
SDHB-associated renal oncocytoma suggests a broadening of the renal phenotype in hereditary paragangliomatosis. | Henderson A | Familial cancer | 2009 | PMID: 19184535 |
Biochemically silent abdominal paragangliomas in patients with mutations in the succinate dehydrogenase subunit B gene. | Timmers HJ | The Journal of clinical endocrinology and metabolism | 2008 | PMID: 18840642 |
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 |
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 |
A case of familial paraganglioma syndrome type 4 caused by a mutation in the SDHB gene. | Drucker AM | Nature clinical practice. Endocrinology & metabolism | 2006 | PMID: 17143317 |
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Text-mined citations for rs397516836 ...
HelpRecord last updated Mar 17, 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.