ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.587G>A (p.Cys196Tyr)
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.587G>A (p.Cys196Tyr)
Variation ID: 230070 Accession: VCV000230070.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17024028 (GRCh38) [ NCBI UCSC ] 1: 17350523 (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 May 29, 2016 Feb 28, 2024 Dec 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.587G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Cys196Tyr missense NC_000001.11:g.17024028C>T NC_000001.10:g.17350523C>T NG_012340.1:g.35143G>A LRG_316:g.35143G>A LRG_316t1:c.587G>A LRG_316p1:p.Cys196Tyr P21912:p.Cys196Tyr - Protein change
- C196Y
- Other names
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- Canonical SPDI
- NC_000001.11:17024027:C: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
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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 |
1253 | 1370 |
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 (1) |
criteria provided, single submitter
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Dec 23, 2021 | RCV000220162.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 7, 2023 | RCV000461924.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 3, 2018 | RCV000479413.3 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV000505388.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2023 | RCV001034642.5 |
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
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782277.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
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Pathogenic
(Dec 03, 2018)
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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: SCV000568587.5
First in ClinVar: Apr 27, 2017 Last updated: Apr 17, 2019 |
Comment:
This pathogenic variant is denoted SDHB c.587G>A at the cDNA level, p.Cys196Tyr (C196Y) at the protein level, and results in the change of a Cysteine … (more)
This pathogenic variant is denoted SDHB c.587G>A at the cDNA level, p.Cys196Tyr (C196Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant has been observed in several individuals and families with both malignant and non-malignant paragangliomas/pheochromocytomas, with at least one tumor showing loss of SDHB protein expression via immunohistochemistry (Neumann 2002, Brouwers 2006, Timmers 2008, Burnichon 2009, Hahn 2009, Dubb 2014, Renella 2014, Michalowska 2015, Jochmanova 2017). Cells transfected with SDHB Cys196Tyr demonstrated SDHB protein loss due to a reduced half-life of the variant protein (Yang 2012). SDHB Cys196Tyr was not observed in large population cohorts (Lek 2016). SDHB Cys196Tyr is located in the 4Fe-4S ferredoxin-type domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic. (less)
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Pathogenic
(Dec 23, 2021)
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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: SCV000273488.6
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.C196Y pathogenic mutation (also known as c.587G>A), located in coding exon 6 of the SDHB gene, results from a G to A substitution at … (more)
The p.C196Y pathogenic mutation (also known as c.587G>A), located in coding exon 6 of the SDHB gene, results from a G to A substitution at nucleotide position 587. The cysteine at codon 196 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation is in the 4Fe-4S ferredoxin-type domain and has been reported in numerous patients with a pheochromocytoma and/or paraganglioma (Neumann HP et al. N. Engl. J. Med. 2002 May; 346(19):1459-66; Amar L et al. J. Clin. Oncol. 2005 Dec; 23(34):8812-8; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar; 91(3):827-36; Brouwers FM et al. J. Clin. Endocrinol. Metab. 2006 Nov; 91(11):4505-9; Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar; 92(3):779-86; Amar L et al. J. Clin. Endocrinol. Metab. 2007 Oct; 92(10):3822-8; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug; 94(8):2817-27; Renella R et al. Fam. Cancer. 2014 Sep;13(3):507-11; Tufton N et al. Endocr. Pathol. 2017 Dec;28(4):320-325). A functional study investigating SDHB missense mutations demonstrated that this variant was associated with accelerated protein degradation and consequent functional insufficiency of the protein (Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). Of note, this alteration is also referred to as c.721G>A in published literature. 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
(Jun 07, 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: SCV004043090.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 26259135, 19576851, 28374168, 31492822, … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 26259135, 19576851, 28374168, 31492822, 35060925]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(Dec 21, 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: SCV000554025.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 196 of the SDHB protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 196 of the SDHB protein (p.Cys196Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pheochromocytomas (PCC) and/or paragangliomas (PGL) many of whom had malignant tumors or family members affected with PCC or PGL (PMID: 17652212, 19064958, 21172883, 23666964, 24781345, 25683602). ClinVar contains an entry for this variant (Variation ID: 230070). 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: SCV000599517.1
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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Tumour detection and outcomes of surveillance screening in SDHB and SDHD pathogenic variant carriers. | White G | Endocrine connections | 2022 | PMID: 35060925 |
Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma-paraganglioma. | Bayley JP | Journal of medical genetics | 2020 | PMID: 31492822 |
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 |
SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations. | Jochmanova I | Journal of cancer research and clinical oncology | 2017 | PMID: 28374168 |
Pituitary Carcinoma in a Patient with an SDHB Mutation. | Tufton N | Endocrine pathology | 2017 | PMID: 28284009 |
Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum. | Niemeijer ND | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 26259135 |
Association of urinary bladder paragangliomas with germline mutations in the SDHB and VHL genes. | Martucci VL | Urologic oncology | 2015 | PMID: 25683602 |
Exploring the association of succinate dehydrogenase complex mutations with lymphoid malignancies. | Renella R | Familial cancer | 2014 | PMID: 24781345 |
A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. | Rattenberry E | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23666964 |
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 |
Bilateral adrenal medullary hyperplasia associated with an SDHB mutation. | Grogan RH | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21172883 |
An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. | van Nederveen FH | The Lancet. Oncology | 2009 | PMID: 19576851 |
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 |
Patient with malignant paraganglioma responding to the multikinase inhibitor sunitinib malate. | Hahn NM | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2009 | PMID: 19064958 |
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 |
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 |
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 |
High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. | Brouwers FM | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16912137 |
Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. | Benn DE | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16317055 |
Genetic testing in pheochromocytoma or functional paraganglioma. | Amar L | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 16314641 |
Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. | Neumann HP | JAMA | 2004 | PMID: 15328326 |
Germ-line mutations in nonsyndromic pheochromocytoma. | Neumann HP | The New England journal of medicine | 2002 | PMID: 12000816 |
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Text-mined citations for rs876658367 ...
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.