ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.689G>A (p.Arg230His)
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.689G>A (p.Arg230His)
Variation ID: 142637 Accession: VCV000142637.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17022684 (GRCh38) [ NCBI UCSC ] 1: 17349179 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 15, 2017 Mar 10, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.689G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Arg230His missense NC_000001.11:g.17022684C>T NC_000001.10:g.17349179C>T NG_012340.1:g.36487G>A LRG_316:g.36487G>A LRG_316t1:c.689G>A LRG_316p1:p.Arg230His - Protein change
- R230H
- Other names
- p.R230H:CGC>CAC
- p.Arg230His
- Canonical SPDI
- NC_000001.11:17022683:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 | ||
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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
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. |
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SDHB | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1253 | 1370 |
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. |
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 17, 2021 | RCV000131970.9 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV000183215.20 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 23, 2022 | RCV000505312.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2024 | RCV000456660.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000762865.4 | |
Pathogenic (2) |
criteria provided, single submitter
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Nov 1, 2016 | RCV000660259.5 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 15, 2010 | RCV001310280.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 28, 2022 | RCV003474782.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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. |
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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782280.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
Pheochromocytoma Carney-Stratakis syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893245.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Jan 26, 2018)
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criteria provided, single submitter
Method: research
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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Academic Department of Medical Genetics, University of Cambridge
Accession: SCV000992188.1
First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019 |
Comment:
Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Clinical Features:
Paraganglioma (present)
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Pathogenic
(Aug 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572270.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: SDHB c.689G>A (p.Arg230His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: SDHB c.689G>A (p.Arg230His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251416 control chromosomes. c.689G>A continues to be widely reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Amar_2005, Brouwers_2006, Amar_2007, Trimmers_2007, Meyer-Rochow_2009, Persu_2008). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function has been ascertained. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000187028.8
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
The p.R230H pathogenic mutation (also known as c.689G>A), located in coding exon 7 of the SDHB gene, results from a G to A substitution at … (more)
The p.R230H pathogenic mutation (also known as c.689G>A), located in coding exon 7 of the SDHB gene, results from a G to A substitution at nucleotide position 689. The arginine at codon 230 is replaced by histidine, an amino acid with highly similar properties. In one study, this mutation was detected in a Mexican kindred in two relatives with head and neck paragangliomas whose tumors demonstrated loss of SDHB protein on immunohistochemistry (Cerecer-Gil et al. Clin Cancer Res 2010 Aug 15; 16(16):4148-54). An individual diagnosed with an autosomal recessive mitochondrial disease and leukoencephalopathy was found to be a compound heterozygote for SDHB p.D48V (c.143A>T) and SDHB p.R230H (c.689G>A) (Grønborg S et al. JIMD Rep. 2017 Sep;33:69-77). Furthermore, p.R230H has been reported in numerous additional kindreds with hereditary paraganglioma-pheochromocytoma, sporadic paraganglioma-pheochromocytoma, and familial renal cell carcinoma (Amar et al. J Clin Oncol. 2005 Dec1; 23(34):8812-8; Said-Al-Naief et al. Head Neck Pathol. 2008 Dec;2(4): 272-8; Ricketts CJ et al. J Urol. 2012; 188:2063-71; Cascón A et al. J Clin Endocrinol Metab. 2009; 94:1701-5; Burnichon N et al. J Clin Endocrinol Metab. 2009; 94:2817-27; Ma X et al. Front Endocrinol (Lausanne) 2020 Dec;11:574662). Two other pathogenic mutations (p.R230C and p.R230L) have also been described at this same codon. Based on available evidence, p.R230H is classified as a pathogenic mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000235635.17
First in ClinVar: Jul 05, 2015 Last updated: Apr 23, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16314641, 24102379, 34906457, 34466344, 20592014, 20208144, 20614293, 23083876, 19454582, 18551016, 25695889, 19393419, 19258401, 16912137, 19576851, 24092654, 24509376, 17200167, 19351833, 26259135, 28374168, 29386252, 30045248, 29909963, 30050099, 30997073, 31365623, 30155846, 32581362, 32859697, 27604842, 27539324, 31666924, 30877234, 32741965, 32561571, 30787465, 31492822, 34750850) (less)
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Pathogenic
(Oct 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Gastrointestinal stromal tumor
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004203033.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224637.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PP4, PM2, PS4_moderate
Number of individuals with the variant: 3
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Likely pathogenic
(Feb 06, 2024)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004243193.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Pathogenic
(Jan 04, 2024)
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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: SCV000554030.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 230 of the SDHB protein (p.Arg230His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 230 of the SDHB protein (p.Arg230His). This variant is present in population databases (rs587782604, gnomAD 0.0009%). This missense change has been observed in individuals with pheochromocytomas, paragangliomas and renal cell carcinomas (PMID: 17200167, 20614293, 23083876, 24509376, 25695889, 26259135, 27539324; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142637). 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%. This variant disrupts the p.Arg230 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14500403, 16314641, 18382370, 19351833, 24939699, 27539324; Invitae). 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)
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Pathogenic
(Apr 01, 2022)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002543875.9
First in ClinVar: Jul 09, 2022 Last updated: Mar 10, 2024 |
Comment:
SDHB: PS4, PM2, PM5, PP1, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Hereditary pheochromocytoma-paraganglioma
Affected status: yes
Allele origin:
germline
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Section on Medical Neuroendocrinolgy, National Institutes of Health
Accession: SCV000599524.1
First in ClinVar: Sep 15, 2017 Last updated: Sep 15, 2017 |
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Pathogenic
(Aug 15, 2010)
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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: SCV004045983.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment on evidence:
Mitochondrial Complex II Deficiency, Nuclear Type 4 For discussion of the c.689G-A transition (c.689G-A, NM_003000.2) in the SDHB gene, resulting in an arg230-to-his (R230H) substitution, … (more)
Mitochondrial Complex II Deficiency, Nuclear Type 4 For discussion of the c.689G-A transition (c.689G-A, NM_003000.2) in the SDHB gene, resulting in an arg230-to-his (R230H) substitution, that was found in compound heterozygous state in a patient with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; 619224) by Gronborg et al. (2017), see 185470.0020. Pheochromocytoma/Paraganglioma Syndrome 4 In 2 patients with head and neck paraganglioms (PPGL4; 115310) from a Mexican family living in Guadalajara, Cerecer-Gil et al. (2010) identified a heterozygous germline c.689G-A transition in the SDHB gene, resulting in an arg230-to-his (R230H) substitution. (less)
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Pathogenic
(Aug 15, 2010)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001500013.2
First in ClinVar: Mar 14, 2021 Last updated: Oct 21, 2023 |
Comment on evidence:
Mitochondrial Complex II Deficiency, Nuclear Type 4 For discussion of the c.689G-A transition (c.689G-A, NM_003000.2) in the SDHB gene, resulting in an arg230-to-his (R230H) substitution, … (more)
Mitochondrial Complex II Deficiency, Nuclear Type 4 For discussion of the c.689G-A transition (c.689G-A, NM_003000.2) in the SDHB gene, resulting in an arg230-to-his (R230H) substitution, that was found in compound heterozygous state in a patient with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; 619224) by Gronborg et al. (2017), see 185470.0020. Pheochromocytoma/Paraganglioma Syndrome 4 In 2 patients with head and neck paraganglioms (PPGL4; 115310) from a Mexican family living in Guadalajara, Cerecer-Gil et al. (2010) identified a heterozygous germline c.689G-A transition in the SDHB gene, resulting in an arg230-to-his (R230H) substitution. (less)
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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 |
Familial SDHB gene mutation in disseminated non-hypoxia-related malignant paraganglioma treated with [(90)Y]Y/[(177)Lu]Lu- DOTATATE. | Łoń I | Intractable & rare diseases research | 2021 | PMID: 34466344 |
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 |
Mutational profile and genotype/phenotype correlation of non-familial pheochromocytoma and paraganglioma. | Albattal S | Oncotarget | 2019 | PMID: 31666924 |
Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance. | Gómez AM | Archives of endocrinology and metabolism | 2019 | PMID: 31365623 |
Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. | Ben Aim L | Journal of medical genetics | 2019 | PMID: 30877234 |
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 |
Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations: Further Cases and Implications for Genetic Counselling. | Grønborg S | JIMD reports | 2017 | PMID: 27604842 |
Germline mutations and genotype-phenotype correlation in Asian Indian patients with pheochromocytoma and paraganglioma. | Pandit R | European journal of endocrinology | 2016 | PMID: 27539324 |
Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum. | Niemeijer ND | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 26259135 |
Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. | Xekouki P | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 25695889 |
[Intrapericardical paraganglioma associated with mutation in succinate dehydrogenase enzyme gene]. | Diéguez Felechosa M | Medicina clinica | 2015 | PMID: 24939699 |
SDHB gene mutation in a carotid body paraganglioma: case report and review of the paraganglioma syndromes. | Peterson LA | Annals of vascular surgery | 2014 | PMID: 24509376 |
Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. | Ricketts CJ | The Journal of urology | 2012 | PMID: 23083876 |
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 |
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 |
Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. | Neumann HP | Cancer research | 2009 | PMID: 19351833 |
Genetics of pheochromocytoma and paraganglioma in Spanish patients. | Cascón A | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19258401 |
Denaturing high performance liquid chromatography detection of SDHB, SDHD, and VHL germline mutations in pheochromocytoma. | Meyer-Rochow GY | The Journal of surgical research | 2009 | PMID: 19215943 |
Hereditary paraganglioma of the nasopharynx. | Said-Al-Naief N | Head and neck pathology | 2008 | PMID: 20614293 |
High prevalence of SDHB mutations in head and neck paraganglioma in Belgium. | Persu A | Journal of hypertension | 2008 | PMID: 18551016 |
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 |
Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. | Amar L | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17652212 |
Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. | Timmers HJ | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17200167 |
High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. | Brouwers FM | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16912137 |
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 |
Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. | Gimenez-Roqueplo AP | Cancer research | 2003 | PMID: 14500403 |
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Text-mined citations for rs587782604 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.