ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.574T>C (p.Cys192Arg)
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.574T>C (p.Cys192Arg)
Variation ID: 186150 Accession: VCV000186150.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17024041 (GRCh38) [ NCBI UCSC ] 1: 17350536 (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 Apr 27, 2017 Feb 28, 2024 Dec 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.574T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Cys192Arg missense NC_000001.11:g.17024041A>G NC_000001.10:g.17350536A>G NG_012340.1:g.35130T>C LRG_316:g.35130T>C LRG_316t1:c.574T>C LRG_316p1:p.Cys192Arg P21912:p.Cys192Arg - Protein change
- C192R
- Other names
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- Canonical SPDI
- NC_000001.11:17024040:A:G
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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 |
1271 | 1385 |
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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May 19, 2022 | RCV000165688.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 4, 2016 | RCV000482399.2 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV000505299.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 31, 2023 | RCV000821774.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2023 | RCV003316045.2 |
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 19, 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: SCV000216426.6
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The p.C192R pathogenic mutation (also known as c.574T>C), located in coding exon 6 of the SDHB gene, results from a T to C substitution at … (more)
The p.C192R pathogenic mutation (also known as c.574T>C), located in coding exon 6 of the SDHB gene, results from a T to C substitution at nucleotide position 574. The cysteine at codon 192 is replaced by arginine, an amino acid with highly dissimilar properties.This alteration has been identified in numerous individuals with paragangliomas and pheochromocytomas (Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Lefebvre S et al. Horm. Metab. Res. 2012 May;44(5):334-8; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27; Klein RD et al. Diagn. Mol. Pathol. 2008 Jun;17(2):94-100; Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar; 92(3):779-86; Michaowska I et al. Kardiochir Torakochirurgia Pol, 2016 Sep;13:276-282). In one series of functional studies, the SDHB p.C192R mutant protein was subject to premature degradation, possibly due to the increased ubiquitination levels observed in the mutant protein compared to wild type SDHB protein (Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). The Cys192 residue plays a vital role coordinating the Fe4S4 cluster and it is believed that alterations at this location would prevent assembly of Complex II (Iverson TM et al. J. Biol. Chem. 2012 Oct;287(42):35430-8). 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
(Feb 08, 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: SCV004018735.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:33628464, 30050099, 27867439, 28503760]. This variant … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:33628464, 30050099, 27867439, 28503760]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(Dec 31, 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: SCV000962543.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 192 of the SDHB protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 192 of the SDHB protein (p.Cys192Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paragangliomas and/or pheochromocytomas many of them were classified as malignant (PMID: 12000816, 17200167, 18382370, 22517554, 25371406, 27785149). ClinVar contains an entry for this variant (Variation ID: 186150). 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
(Oct 04, 2016)
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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: SCV000568588.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
This pathogenic variant is denoted SDHB c.574T>C at the cDNA level, p.Cys192Arg (C192R) at the protein level, and results in the change of a Cysteine … (more)
This pathogenic variant is denoted SDHB c.574T>C at the cDNA level, p.Cys192Arg (C192R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has been reported in numerous individuals with parangangliomas or pheochromocytomas, many of which were metastatic (Neumann 2002, Timmers 2007, Burnichon 2009, Hensen 2012, Lefebvre 2012, Michalowska 2015, Sue 2015). SDHB Cys192Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHB Cys192Arg occurs at a position that is conserved across species and is located in the 4Fe-4S ferredoxin-type domain (Uniprot). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic. (less)
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Likely 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: SCV000599518.1
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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Hereditary Paraganglioma in an Omani Family. | Pambinezhthu F | Oman medical journal | 2021 | PMID: 33628464 |
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 |
The penetrance of paraganglioma and pheochromocytoma in SDHB germline mutation carriers. | Rijken JA | Clinical genetics | 2018 | PMID: 28503760 |
Evaluation of Head and Neck Paragangliomas by Computed Tomography in Patients with Pheochromocytoma-Paraganglioma Syndromes. | Michałowska I | Polish journal of radiology | 2016 | PMID: 27867439 |
Mediastinal paragangliomas related to SDHx gene mutations. | Michałowska I | Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery | 2016 | PMID: 27785149 |
Lack of utility of SDHB mutation testing in adrenergic metastatic phaeochromocytoma. | Sue M | European journal of endocrinology | 2015 | PMID: 25371406 |
Structural basis for malfunction in complex II. | Iverson TM | The Journal of biological chemistry | 2012 | PMID: 22904323 |
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 |
Screening of mutations in genes that predispose to hereditary paragangliomas and pheochromocytomas. | Lefebvre S | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2012 | PMID: 22517554 |
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 |
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 |
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 rs786202732 ...
HelpRecord last updated Apr 15, 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.