This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the SDHB protein (p.Arg46Gln). This variant is present in population databases (rs772551056, gnomAD 0.0009%). This missense change has been observed in individuals with pheochromocytoma, paraganglioma, gastrointestinal stromal tumors, adrenal tumors, and renal cancer (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968). ClinVar contains an entry for this variant (Variation ID: 183793). 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, 25972245, 26719882). This variant disrupts the p.Arg46 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14500403, 15328326, 25972245). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.137G>A (p.Arg46Gln)
Germline
Classification
Help
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.
(18)
Help
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.
Pathogenic/Likely pathogenic
18
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003000.3(SDHB):c.137G>A (p.Arg46Gln)
Variation ID: 183793 Accession: VCV000183793.50
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p36.13 1: 17044824 (GRCh38) [ NCBI UCSC ] 1: 17371319 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 6, 2016 Oct 20, 2024 Jan 27, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003000.3:c.137G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Arg46Gln missense NC_000001.11:g.17044824C>T NC_000001.10:g.17371319C>T NG_012340.1:g.14347G>A LRG_316:g.14347G>A LRG_316t1:c.137G>A LRG_316p1:p.Arg46Gln P21912:p.Arg46Gln - Protein change
- R46Q
- Other names
-
p.R46Q:CGA>CAA
- Canonical SPDI
- NC_000001.11:17044823:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
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. |
|||
| SDHB | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1327 | 1445 | |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 8, 2021 | RCV000162578.9 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2022 | RCV000183217.31 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2023 | RCV000232432.12 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 11, 2023 | RCV000505310.13 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
Jan 1, 2017 | RCV000722045.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763273.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 27, 2024 | RCV000627748.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 8, 2023 | RCV003474845.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 28, 2020 | RCV001530203.3 |
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
Help
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Paragangliomas 4
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782272.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
|
|
|
Likely pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: research
|
SDHB-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Snyder Lab, Genetics Department, Stanford University
Accession: SCV000853087.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Paragangliomas 4
Pheochromocytoma Carney-Stratakis syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893917.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Aug 09, 2018)
|
criteria provided, single submitter
Method: research
|
Paragangliomas 4
Affected status: unknown
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI_GT
Accession: SCV000993583.1 First in ClinVar: Sep 26, 2019 Last updated: Sep 26, 2019 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 28, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Pheochromocytoma
Affected status: yes
Allele origin:
germline
|
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital
Accession: SCV001739500.1
First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Ethnicity/Population group: East asia
Geographic origin: China
Testing laboratory: Liwei's Lab
|
|
|
Likely pathogenic
(Feb 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Paragangliomas 4
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677773.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Jan 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000287759.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the SDHB protein (p.Arg46Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the SDHB protein (p.Arg46Gln). This variant is present in population databases (rs772551056, gnomAD 0.0009%). This missense change has been observed in individuals with pheochromocytoma, paraganglioma, gastrointestinal stromal tumors, adrenal tumors, and renal cancer (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968). ClinVar contains an entry for this variant (Variation ID: 183793). 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, 25972245, 26719882). This variant disrupts the p.Arg46 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14500403, 15328326, 25972245). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary pheochromocytoma-paraganglioma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004821943.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and/or pheochromocytoma (PMID: 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 23512077, 24102379, 24659481, 28374168, 28503760, 29386252, 29951630, 31492822, 32741965, 34439168), and observed in individuals affected with gastrointestinal stromal tumors (GIST; PMID: 23282968), renal cell carcinoma (RCC; PMID: 23083876) and gastric adenocarcinoma (PMID: 32963463). This variant has been identified in 1/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Apr 29, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary pheochromocytoma-paraganglioma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712031.3
First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
|
|
|
Pathogenic
(Dec 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000212994.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.R46Q pathogenic mutation (also known as c.137G>A), located in coding exon 2 of the SDHB gene, results from a G to A substitution at … (more)
The p.R46Q pathogenic mutation (also known as c.137G>A), located in coding exon 2 of the SDHB gene, results from a G to A substitution at nucleotide position 137. The arginine at codon 46 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been seen in multiple patients with pheochromocytoma, paraganglioma, and/or GIST (Gimenez-Roqueplo AP et al. J. Clin. Endocrinol. Metab. 2002 Oct;87:4771-4; Benn DE et al. Oncogene, 2003 Mar;22:1358-64; Neumann HP et al. JAMA, 2004 Aug;292:943-51; Benn DE et al. J Clin Endocrinol Metab, 2006 Mar;91:827-36; Timmers HJ et al. J Clin Endocrinol Metab, 2008 Dec;93:4826-32; Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40; McInerney-Leo AM et al. Clin Endocrinol (Oxf), 2014 Jan;80:25-33; Kimura N et al. Endocr Relat Cancer, 2014 Jun;21:L13-6; Rijken JA et al. Clin. Genet. 2017 May; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394; Ji K et al. Chin J Cancer Res, 2020 Aug;32:508-515; Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Bayley JP et al. J Med Genet, 2020 02;57:96-103; Yonamine M et al. Cancers (Basel), 2021 Aug;13). This mutation has been shown to increase protein degradation and to reduce mutant protein half-life in transfected cell lines (Saxena N et al. J. Natl. Cancer Inst. 2016 Jan;108; Yang C et al. FASEB J, 2012 Nov;26:4506-16). In addition, in vitro analyses have shown significantly reduced mitochondrial SDHB expression and a reduction in SDHB enzymatic activity compared to wild type (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Functional analysis of R46Q demonstrated complete loss of SDHB-SDHAF3 interaction (Dwight T et al. BMC Cancer, 2017 Jul;17:497). Structural analysis showed that the R46Q alteration impaired iron incorporation and Complex II biogenesis (Maio N et al. Cell Metab, 2014 Mar;19:445-57). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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|
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Pathogenic
(Nov 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Gastrointestinal stromal tumor
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004203032.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Mar 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000886095.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The SDHB c.137G>A; p.Arg46Gln variant (rs772551056) has been observed in individuals and families affected with pheochromocytoma, paraganglioma, adrenal tumors, and renal cell carcinoma (Benn 2003, … (more)
The SDHB c.137G>A; p.Arg46Gln variant (rs772551056) has been observed in individuals and families affected with pheochromocytoma, paraganglioma, adrenal tumors, and renal cell carcinoma (Benn 2003, Gimenez-Roqueplo 2003, Neumann 2004, Ricketts 2012). This variant has been reported as pathogenic by several laboratories in ClinVar (Variation ID: 183793) and has been observed in the general population at a low overall frequency of 0.0004% (1/246124 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (p.Arg46Gly) has been observed in individuals affected with extra-adrenal pheochromocytoma and adrenal tumors and is considered pathogenic (Gimenez-Roqueplo 2003, Neumann 2004). The arginine at codon 46 is highly conserved and computational algorithms (SIFT, PolyPhen-2) predict this variant to be deleterious. Further, functional analyses of p.Arg46Gln demonstrate decreased succinate dehydrogenase expression and activity and increased hypoxia-inducible factors (Saxena 2016). Based on the above information, this variant is considered pathogenic. References: Benn D et al. Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas. Oncogene. 2003 Mar 6;22(9):1358-64. Gimenez-Roqueplo A et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003 Sep 1;63(17):5615-21. Neumann H et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. Ricketts C et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol. 2012 Dec;188(6):2063-71. Saxena N et al. SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. J Natl Cancer Inst. 2016 Jan; 108(1): djv287. (less)
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|
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Pathogenic
(Mar 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000235637.15
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: reduced protein stability, decreased succinate dehydrogenase activity, and increased hypoxia-inducible factors (Giminez-Roqueplo et al., 2002; Yang et al., … (more)
Published functional studies demonstrate a damaging effect: reduced protein stability, decreased succinate dehydrogenase activity, and increased hypoxia-inducible factors (Giminez-Roqueplo et al., 2002; Yang et al., 2012; Saxena et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18728283, 23083876, 15987702, 24659481, 28738844, 24102379, 31447099, 12364472, 26464466, 15476441, 22835832, 19454582, 12618761, 16317055, 17102082, 23512077, 14500403, 23282968, 23175444, 19522823, 18362451, 18840642, 19576851, 16314641, 26719882, 28374168, 27700540, 25972245, 28503760, 28944243, 29386252, 28152038, 29951630, 30487145, 30877234, 28490599, 30122538, 30694796, 31492822, 32741965) (less)
|
|
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Pathogenic
(Apr 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Paragangliomas 4
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004045422.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22677546, 26719882, 25972245]. This variant is expected to disrupt protein structure … (more)
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22677546, 26719882, 25972245]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12618761, 28374168, 23512077, 34439168]. (less)
|
|
|
Pathogenic
(Jun 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Paragangliomas 4
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004362282.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and/or pheochromocytoma (PMID: 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 23512077, 24102379, 24659481, 28374168, 28503760, 29386252, 29951630, 31492822, 32741965, 34439168), and observed in individuals affected with gastrointestinal stromal tumors (GIST; PMID: 23282968), renal cell carcinoma (RCC; PMID: 23083876) and gastric adenocarcinoma (PMID: 32963463). This variant has been identified in 1/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002496465.18
First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Hereditary pheochromocytoma-paraganglioma
Affected status: yes
Allele origin:
germline
|
Section on Medical Neuroendocrinolgy, National Institutes of Health
Accession: SCV000599484.1
First in ClinVar: Sep 15, 2017 Last updated: Sep 15, 2017 |
|
|
|
Pathogenic
(Jul 19, 2024)
|
no assertion criteria provided
Method: clinical testing
|
SDHB-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005358433.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The SDHB c.137G>A variant is predicted to result in the amino acid substitution p.Arg46Gln. This variant has been reported in several unrelated individuals with pheochromocytoma, … (more)
The SDHB c.137G>A variant is predicted to result in the amino acid substitution p.Arg46Gln. This variant has been reported in several unrelated individuals with pheochromocytoma, paraganglioma, and gastrointestinal stromal tumors (see for example, Gimenez-Roqueplo et al. 2002. PubMed ID: 12364472; Gimenez-Roqueplo et al. 2003. PubMed ID: 14500403 Benn et al. 2003. PubMed ID: 12618761; Neumann et al. 2004. PubMed ID: 15328326; Miettinen et al. 2013. PubMed ID: 23282968). Functional in vitro assays show that this variant leads to protein instability (Yang et al. 2012. PubMed ID: 22835832; Saxena et al. 2016. PubMed ID: 26719882). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, it is reported as likely pathogenic/pathogenic by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/183793/). We classify this variant as pathogenic. (less)
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Comment:
Comment:
This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and/or pheochromocytoma (PMID: 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 23512077, 24102379, 24659481, 28374168, 28503760, 29386252, 29951630, 31492822, 32741965, 34439168), and observed in individuals affected with gastrointestinal stromal tumors (GIST; PMID: 23282968), renal cell carcinoma (RCC; PMID: 23083876) and gastric adenocarcinoma (PMID: 32963463). This variant has been identified in 1/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Comment:
The p.R46Q pathogenic mutation (also known as c.137G>A), located in coding exon 2 of the SDHB gene, results from a G to A substitution at nucleotide position 137. The arginine at codon 46 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been seen in multiple patients with pheochromocytoma, paraganglioma, and/or GIST (Gimenez-Roqueplo AP et al. J. Clin. Endocrinol. Metab. 2002 Oct;87:4771-4; Benn DE et al. Oncogene, 2003 Mar;22:1358-64; Neumann HP et al. JAMA, 2004 Aug;292:943-51; Benn DE et al. J Clin Endocrinol Metab, 2006 Mar;91:827-36; Timmers HJ et al. J Clin Endocrinol Metab, 2008 Dec;93:4826-32; Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40; McInerney-Leo AM et al. Clin Endocrinol (Oxf), 2014 Jan;80:25-33; Kimura N et al. Endocr Relat Cancer, 2014 Jun;21:L13-6; Rijken JA et al. Clin. Genet. 2017 May; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394; Ji K et al. Chin J Cancer Res, 2020 Aug;32:508-515; Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Bayley JP et al. J Med Genet, 2020 02;57:96-103; Yonamine M et al. Cancers (Basel), 2021 Aug;13). This mutation has been shown to increase protein degradation and to reduce mutant protein half-life in transfected cell lines (Saxena N et al. J. Natl. Cancer Inst. 2016 Jan;108; Yang C et al. FASEB J, 2012 Nov;26:4506-16). In addition, in vitro analyses have shown significantly reduced mitochondrial SDHB expression and a reduction in SDHB enzymatic activity compared to wild type (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Functional analysis of R46Q demonstrated complete loss of SDHB-SDHAF3 interaction (Dwight T et al. BMC Cancer, 2017 Jul;17:497). Structural analysis showed that the R46Q alteration impaired iron incorporation and Complex II biogenesis (Maio N et al. Cell Metab, 2014 Mar;19:445-57). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The SDHB c.137G>A; p.Arg46Gln variant (rs772551056) has been observed in individuals and families affected with pheochromocytoma, paraganglioma, adrenal tumors, and renal cell carcinoma (Benn 2003, Gimenez-Roqueplo 2003, Neumann 2004, Ricketts 2012). This variant has been reported as pathogenic by several laboratories in ClinVar (Variation ID: 183793) and has been observed in the general population at a low overall frequency of 0.0004% (1/246124 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (p.Arg46Gly) has been observed in individuals affected with extra-adrenal pheochromocytoma and adrenal tumors and is considered pathogenic (Gimenez-Roqueplo 2003, Neumann 2004). The arginine at codon 46 is highly conserved and computational algorithms (SIFT, PolyPhen-2) predict this variant to be deleterious. Further, functional analyses of p.Arg46Gln demonstrate decreased succinate dehydrogenase expression and activity and increased hypoxia-inducible factors (Saxena 2016). Based on the above information, this variant is considered pathogenic. References: Benn D et al. Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas. Oncogene. 2003 Mar 6;22(9):1358-64. Gimenez-Roqueplo A et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003 Sep 1;63(17):5615-21. Neumann H et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. Ricketts C et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol. 2012 Dec;188(6):2063-71. Saxena N et al. SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. J Natl Cancer Inst. 2016 Jan; 108(1): djv287.
Comment:
Published functional studies demonstrate a damaging effect: reduced protein stability, decreased succinate dehydrogenase activity, and increased hypoxia-inducible factors (Giminez-Roqueplo et al., 2002; Yang et al., 2012; Saxena et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18728283, 23083876, 15987702, 24659481, 28738844, 24102379, 31447099, 12364472, 26464466, 15476441, 22835832, 19454582, 12618761, 16317055, 17102082, 23512077, 14500403, 23282968, 23175444, 19522823, 18362451, 18840642, 19576851, 16314641, 26719882, 28374168, 27700540, 25972245, 28503760, 28944243, 29386252, 28152038, 29951630, 30487145, 30877234, 28490599, 30122538, 30694796, 31492822, 32741965)
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22677546, 26719882, 25972245]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12618761, 28374168, 23512077, 34439168].
Comment:
This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and/or pheochromocytoma (PMID: 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 23512077, 24102379, 24659481, 28374168, 28503760, 29386252, 29951630, 31492822, 32741965, 34439168), and observed in individuals affected with gastrointestinal stromal tumors (GIST; PMID: 23282968), renal cell carcinoma (RCC; PMID: 23083876) and gastric adenocarcinoma (PMID: 32963463). This variant has been identified in 1/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The SDHB c.137G>A variant is predicted to result in the amino acid substitution p.Arg46Gln. This variant has been reported in several unrelated individuals with pheochromocytoma, paraganglioma, and gastrointestinal stromal tumors (see for example, Gimenez-Roqueplo et al. 2002. PubMed ID: 12364472; Gimenez-Roqueplo et al. 2003. PubMed ID: 14500403 Benn et al. 2003. PubMed ID: 12618761; Neumann et al. 2004. PubMed ID: 15328326; Miettinen et al. 2013. PubMed ID: 23282968). Functional in vitro assays show that this variant leads to protein instability (Yang et al. 2012. PubMed ID: 22835832; Saxena et al. 2016. PubMed ID: 26719882). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, it is reported as likely pathogenic/pathogenic by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/183793/). We classify this variant as pathogenic.
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. |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the SDHB protein (p.Arg46Gln). This variant is present in population databases (rs772551056, gnomAD 0.0009%). This missense change has been observed in individuals with pheochromocytoma, paraganglioma, gastrointestinal stromal tumors, adrenal tumors, and renal cancer (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968). ClinVar contains an entry for this variant (Variation ID: 183793). 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, 25972245, 26719882). This variant disrupts the p.Arg46 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14500403, 15328326, 25972245). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and/or pheochromocytoma (PMID: 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 23512077, 24102379, 24659481, 28374168, 28503760, 29386252, 29951630, 31492822, 32741965, 34439168), and observed in individuals affected with gastrointestinal stromal tumors (GIST; PMID: 23282968), renal cell carcinoma (RCC; PMID: 23083876) and gastric adenocarcinoma (PMID: 32963463). This variant has been identified in 1/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Comment:
The p.R46Q pathogenic mutation (also known as c.137G>A), located in coding exon 2 of the SDHB gene, results from a G to A substitution at nucleotide position 137. The arginine at codon 46 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been seen in multiple patients with pheochromocytoma, paraganglioma, and/or GIST (Gimenez-Roqueplo AP et al. J. Clin. Endocrinol. Metab. 2002 Oct;87:4771-4; Benn DE et al. Oncogene, 2003 Mar;22:1358-64; Neumann HP et al. JAMA, 2004 Aug;292:943-51; Benn DE et al. J Clin Endocrinol Metab, 2006 Mar;91:827-36; Timmers HJ et al. J Clin Endocrinol Metab, 2008 Dec;93:4826-32; Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40; McInerney-Leo AM et al. Clin Endocrinol (Oxf), 2014 Jan;80:25-33; Kimura N et al. Endocr Relat Cancer, 2014 Jun;21:L13-6; Rijken JA et al. Clin. Genet. 2017 May; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394; Ji K et al. Chin J Cancer Res, 2020 Aug;32:508-515; Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Bayley JP et al. J Med Genet, 2020 02;57:96-103; Yonamine M et al. Cancers (Basel), 2021 Aug;13). This mutation has been shown to increase protein degradation and to reduce mutant protein half-life in transfected cell lines (Saxena N et al. J. Natl. Cancer Inst. 2016 Jan;108; Yang C et al. FASEB J, 2012 Nov;26:4506-16). In addition, in vitro analyses have shown significantly reduced mitochondrial SDHB expression and a reduction in SDHB enzymatic activity compared to wild type (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Functional analysis of R46Q demonstrated complete loss of SDHB-SDHAF3 interaction (Dwight T et al. BMC Cancer, 2017 Jul;17:497). Structural analysis showed that the R46Q alteration impaired iron incorporation and Complex II biogenesis (Maio N et al. Cell Metab, 2014 Mar;19:445-57). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The SDHB c.137G>A; p.Arg46Gln variant (rs772551056) has been observed in individuals and families affected with pheochromocytoma, paraganglioma, adrenal tumors, and renal cell carcinoma (Benn 2003, Gimenez-Roqueplo 2003, Neumann 2004, Ricketts 2012). This variant has been reported as pathogenic by several laboratories in ClinVar (Variation ID: 183793) and has been observed in the general population at a low overall frequency of 0.0004% (1/246124 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (p.Arg46Gly) has been observed in individuals affected with extra-adrenal pheochromocytoma and adrenal tumors and is considered pathogenic (Gimenez-Roqueplo 2003, Neumann 2004). The arginine at codon 46 is highly conserved and computational algorithms (SIFT, PolyPhen-2) predict this variant to be deleterious. Further, functional analyses of p.Arg46Gln demonstrate decreased succinate dehydrogenase expression and activity and increased hypoxia-inducible factors (Saxena 2016). Based on the above information, this variant is considered pathogenic. References: Benn D et al. Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas. Oncogene. 2003 Mar 6;22(9):1358-64. Gimenez-Roqueplo A et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003 Sep 1;63(17):5615-21. Neumann H et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. Ricketts C et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol. 2012 Dec;188(6):2063-71. Saxena N et al. SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. J Natl Cancer Inst. 2016 Jan; 108(1): djv287.
Comment:
Published functional studies demonstrate a damaging effect: reduced protein stability, decreased succinate dehydrogenase activity, and increased hypoxia-inducible factors (Giminez-Roqueplo et al., 2002; Yang et al., 2012; Saxena et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18728283, 23083876, 15987702, 24659481, 28738844, 24102379, 31447099, 12364472, 26464466, 15476441, 22835832, 19454582, 12618761, 16317055, 17102082, 23512077, 14500403, 23282968, 23175444, 19522823, 18362451, 18840642, 19576851, 16314641, 26719882, 28374168, 27700540, 25972245, 28503760, 28944243, 29386252, 28152038, 29951630, 30487145, 30877234, 28490599, 30122538, 30694796, 31492822, 32741965)
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22677546, 26719882, 25972245]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12618761, 28374168, 23512077, 34439168].
Comment:
This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and/or pheochromocytoma (PMID: 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 23512077, 24102379, 24659481, 28374168, 28503760, 29386252, 29951630, 31492822, 32741965, 34439168), and observed in individuals affected with gastrointestinal stromal tumors (GIST; PMID: 23282968), renal cell carcinoma (RCC; PMID: 23083876) and gastric adenocarcinoma (PMID: 32963463). This variant has been identified in 1/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The SDHB c.137G>A variant is predicted to result in the amino acid substitution p.Arg46Gln. This variant has been reported in several unrelated individuals with pheochromocytoma, paraganglioma, and gastrointestinal stromal tumors (see for example, Gimenez-Roqueplo et al. 2002. PubMed ID: 12364472; Gimenez-Roqueplo et al. 2003. PubMed ID: 14500403 Benn et al. 2003. PubMed ID: 12618761; Neumann et al. 2004. PubMed ID: 15328326; Miettinen et al. 2013. PubMed ID: 23282968). Functional in vitro assays show that this variant leads to protein instability (Yang et al. 2012. PubMed ID: 22835832; Saxena et al. 2016. PubMed ID: 26719882). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, it is reported as likely pathogenic/pathogenic by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/183793/). We classify this variant as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma. | Yonamine M | Cancers | 2021 | PMID: 34439168 |
| Characteristics of cancer susceptibility genes mutations in 282 patients with gastric adenocarcinoma. | Ji K | Chinese journal of cancer research = Chung-kuo yen cheng yen chiu | 2020 | PMID: 32963463 |
| 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 |
| Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma-paraganglioma. | Bayley JP | Journal of medical genetics | 2020 | PMID: 31492822 |
| Nationwide study of patients with head and neck paragangliomas carrying SDHB germline mutations. | Rijken JA | BJS open | 2018 | PMID: 29951630 |
| 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 |
| The penetrance of paraganglioma and pheochromocytoma in SDHB germline mutation carriers. | Rijken JA | Clinical genetics | 2018 | PMID: 28503760 |
| Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma. | Dwight T | BMC cancer | 2017 | PMID: 28738844 |
| SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations. | Jochmanova I | Journal of cancer research and clinical oncology | 2017 | PMID: 28374168 |
| SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. | Saxena N | Journal of the National Cancer Institute | 2016 | PMID: 26719882 |
| Structural and functional consequences of succinate dehydrogenase subunit B mutations. | Kim E | Endocrine-related cancer | 2015 | PMID: 25972245 |
| Clinicopathological study of SDHB mutation-related pheochromocytoma and sympathetic paraganglioma. | Kimura N | Endocrine-related cancer | 2014 | PMID: 24659481 |
| Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster delivery. | Maio N | Cell metabolism | 2014 | PMID: 24606901 |
| Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas. | McInerney-Leo AM | Clinical endocrinology | 2014 | PMID: 24102379 |
| Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. | Fishbein L | Annals of surgical oncology | 2013 | PMID: 23512077 |
| 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 |
| Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. | Panizza E | Human molecular genetics | 2013 | PMID: 23175444 |
| Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. | Ricketts CJ | The Journal of urology | 2012 | PMID: 23083876 |
| 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 |
| Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. | Xiao M | Genes & development | 2012 | PMID: 22677546 |
| Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. | Ricketts CJ | Human mutation | 2010 | PMID: 19802898 |
| 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 |
| R46Q mutation in the succinate dehydrogenase B gene (SDHB) in a Japanese family with both abdominal and thoracic paraganglioma following metastasis. | Takekoshi K | Endocrine journal | 2008 | PMID: 18362451 |
| Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients. | Castellano M | Annals of the New York Academy of Sciences | 2006 | PMID: 17102082 |
| 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 |
| Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. | Gimenez-Roqueplo AP | Cancer research | 2003 | PMID: 14500403 |
| Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas. | Benn DE | Oncogene | 2003 | PMID: 12618761 |
| 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 |
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Text-mined citations for rs772551056 ...
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Record last updated Oct 20, 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.