ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.590C>G (p.Pro197Arg)
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.590C>G (p.Pro197Arg)
Variation ID: 12779 Accession: VCV000012779.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17024025 (GRCh38) [ NCBI UCSC ] 1: 17350520 (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 Dec 29, 2015 Feb 28, 2024 Aug 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.590C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Pro197Arg missense NC_000001.11:g.17024025G>C NC_000001.10:g.17350520G>C NG_012340.1:g.35146C>G LRG_316:g.35146C>G LRG_316t1:c.590C>G LRG_316p1:p.Pro197Arg P21912:p.Pro197Arg - Protein change
- P197R
- Other names
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- Canonical SPDI
- NC_000001.11:17024024:G:C
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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 0.00000
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 | 1366 |
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
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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Likely pathogenic (2) |
no assertion criteria provided
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- | RCV000030623.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2020 | RCV000213984.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 30, 2023 | RCV000465474.13 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 17, 2023 | RCV000013617.33 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 7, 2022 | RCV001810856.14 |
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
(Jan 16, 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: SCV000273721.7
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.P197R pathogenic mutation (also known as c.590C>G), located in coding exon 6 of the SDHB gene, results from a C to G substitution at … (more)
The p.P197R pathogenic mutation (also known as c.590C>G), located in coding exon 6 of the SDHB gene, results from a C to G substitution at nucleotide position 590. The proline at codon 197 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals/multiple families diagnosed with paragangliomas and/or pheochromocytomas (Astuti D et al. Am. J. Hum. Genet. 2001 Jul;69:49-54; Gimenez-Roqueplo AP et al. J. Clin. Endocrinol. Metab. 2002 Oct;87:4771-4; Lawrence JK et al. Hormones (Athens) 2004. 3(2):127-31; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435; Jawed I et al. Cell. Mol. Neurobiol. 2018 Jul;38:1099-1106; Rijken JA et al. BJS Open. 2018 Apr;2:62-69), as well as an individual diagnosed with a GIST (Schrader KA et al. JAMA Oncol. 2016 Jan;2:104-11). In one study, PGL-PCC tumor studies of an individual known to carry the p.P197R alteration showed negative SDHB protein expression on IHC (van Nederveen FH et al. Lancet Oncol. 2009 Aug;10:764-71). Authors of one study showed that the p.P197R alteration led to mitochondrial expression levels and SDH enzyme activity levels similar to that of wild type cells in vitro; however structural modeling predicted this alteration would affect the function of the electron path in the electron transport chain (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Based on internal structural analysis, P197R introduces a large, positively-charged side-chain into a functionally critical region of SDHB, and is likely to disrupt both ubiquinone binding and reduction of ubiquinone (Sun F et al. Cell. 2005 Jul;121:1043-57; Yankovskaya V et al. Science. 2003 Jan;299:700-4; Guo J et al. J. Biol. Chem. 2003 Nov;278:47629-35). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Of note, this variant is also called p.P198R (c.724C>G) in some 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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Likely pathogenic
(Jul 07, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226484.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1_moderate, PP3, PP4, PM2, PS4_moderate
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 12, 2019)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001158579.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 26, 2021 |
Comment:
The SDHB c.590C>G; p.Pro197Arg variant (rs74315367) is reported in the literature in multiple individuals and families affected with hereditary paraganglioma/pheochromocytoma syndrome, though it has also … (more)
The SDHB c.590C>G; p.Pro197Arg variant (rs74315367) is reported in the literature in multiple individuals and families affected with hereditary paraganglioma/pheochromocytoma syndrome, though it has also been reported in several asymptomatic carriers (Astuti 2001, Lawrence 2004, Niemeijer 2017, Rijken 2018, Srirangalingam 2008). Another variant at this codon, p.Pro197Ser, is also reported in individuals with paragangliomas (Hermsen 2010, Lima 2007). The p.Pro197Arg variant is reported in ClinVar (Variation ID: 12779). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 197 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. While biochemical characterization of p.Pro197Arg variant protein showed no effect on SDH activity or association with SDHA protein, in silico analysis of this variant suggested defective electron transport and generation of reactive oxygen species (Kim 2015). Based on available information, the p.Pro197Arg variant is considered to be likely pathogenic. REFERENCES Astuti D et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001 Jul;69(1):49-54. Hermsen MA et al. Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management. Cell Oncol. 2010 Jan 1;32(4):275-83. Kim E et al. Structural and functional consequences of succinate dehydrogenase subunit B mutations. Endocr Relat Cancer. 2015 Jun;22(3):387-97. Lawrence JK et al. Familial paraganglioma: a novel presentation of a case and response to therapy with radiolabelled MIBG. Hormones (Athens). 2004 Apr-Jun;3(2):127-31. Lima J et al. High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain: mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathological correlations. J Clin Endocrinol Metab. 2007 Dec;92(12):4853-64. Niemeijer ND et al. The phenotype of SDHB germline mutation carriers: a nationwide study. Eur J Endocrinol. 2017 Aug;177(2):115-125. Rijken JA et al. Nationwide study of patients with head and neck paragangliomas carrying SDHB germline mutations. BJS Open. 2018 Feb 6;2(2):62-69. Srirangalingam U et al. Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers. Clin Endocrinol (Oxf). 2008 Oct;69(4):587-96. (less)
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Pathogenic
(Aug 30, 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: SCV000553988.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This variant disrupts the p.Pro197 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been observed in individuals with SDHB-related conditions (PMID: … (more)
This variant disrupts the p.Pro197 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been observed in individuals with SDHB-related conditions (PMID: 20208144), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change does not substantially affect SDHB function (PMID: 18519664, 25972245, 28738844). 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. ClinVar contains an entry for this variant (Variation ID: 12779). This missense change has been observed in individuals with gastrointestinal stromal tumor, paraganglioma, and/or pheochromocytoma (PMID: 11404820, 14974914, 18419787, 21348866, 25047027, 26556299, 27542510, 28374168; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs74315367, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 197 of the SDHB protein (p.Pro197Arg). For these reasons, this variant has been classified as 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: SCV000599521.1
First in ClinVar: Dec 29, 2015 Last updated: Dec 29, 2015 |
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Pathogenic
(Oct 17, 2023)
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no assertion criteria provided
Method: literature only
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PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033864.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
In a family containing 3 individuals with familial extraadrenal pheochromocytoma and without evidence of cervical paragangliomas (PPGL4; 115310), Astuti et al. (2001) identified a heterozygous … (more)
In a family containing 3 individuals with familial extraadrenal pheochromocytoma and without evidence of cervical paragangliomas (PPGL4; 115310), Astuti et al. (2001) identified a heterozygous 724C-G transversion in exon 6 of the SDHB gene, resulting in a pro197-to-arg (P197R) substitution. This proline is conserved throughout all living species analyzed, from human to rat, Drosophila, yeast, and E. coli. This mutation was originally published as PRO198ARG; the corrected numbering appeared in an erratum. (less)
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not provided
(Oct 02, 2015)
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no classification provided
Method: clinical testing
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Hereditary Paraganglioma-Pheochromocytoma Syndromes
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053301.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 29, 2015 |
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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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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 |
Paraganglioma and other tumour detection rates in individuals with SDHx pathogenic variants by age of diagnosis and after the age of 50. | Greenberg SE | Clinical endocrinology | 2021 | PMID: 34255389 |
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 |
Characterization of Malignant Head and Neck Paragangliomas at a Single Institution Across Multiple Decades. | McCrary HC | JAMA otolaryngology-- head & neck surgery | 2019 | PMID: 31194233 |
Nationwide study of patients with head and neck paragangliomas carrying SDHB germline mutations. | Rijken JA | BJS open | 2018 | PMID: 29951630 |
Continued Tumor Reduction of Metastatic Pheochromocytoma/Paraganglioma Harboring Succinate Dehydrogenase Subunit B Mutations with Cyclical Chemotherapy. | Jawed I | Cellular and molecular neurobiology | 2018 | PMID: 29623478 |
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 |
Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma. | Dwight T | BMC cancer | 2017 | PMID: 28738844 |
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 |
Succinate Dehydrogenase B (SDHB)-Associated Bladder Paragangliomas. | Srirangalingam U | Clinical genitourinary cancer | 2017 | PMID: 27542510 |
Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. | Schrader KA | JAMA oncology | 2016 | PMID: 26556299 |
Structural and functional consequences of succinate dehydrogenase subunit B mutations. | Kim E | Endocrine-related cancer | 2015 | PMID: 25972245 |
Phenotype of SDHB mutation carriers in the Netherlands. | van Hulsteijn LT | Familial cancer | 2014 | PMID: 25047027 |
High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. | Hensen EF | Clinical genetics | 2012 | PMID: 21348866 |
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 |
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 |
Cells silenced for SDHB expression display characteristic features of the tumor phenotype. | Cervera AM | Cancer research | 2008 | PMID: 18519664 |
Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers. | Srirangalingam U | Clinical endocrinology | 2008 | PMID: 18419787 |
Crystal structure of mitochondrial respiratory membrane protein complex II. | Sun F | Cell | 2005 | PMID: 15989954 |
Familial paraganglioma: a novel presentation of a case and response to therapy with radiolabelled MIBG. | Lawrence JK | Hormones (Athens, Greece) | 2004 | PMID: 16982587 |
Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. | Astuti D | Clinical endocrinology | 2003 | PMID: 14974914 |
The ubiquinone-binding site of the Saccharomyces cerevisiae succinate-ubiquinone oxidoreductase is a source of superoxide. | Guo J | The Journal of biological chemistry | 2003 | PMID: 13129931 |
Architecture of succinate dehydrogenase and reactive oxygen species generation. | Yankovskaya V | Science (New York, N.Y.) | 2003 | PMID: 12560550 |
Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. | Gimenez-Roqueplo AP | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 12364472 |
Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. | Astuti D | American journal of human genetics | 2001 | PMID: 11404820 |
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Text-mined citations for rs74315367 ...
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.