ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.689G>T (p.Arg230Leu)
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>T (p.Arg230Leu)
Variation ID: 184933 Accession: VCV000184933.17
- 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 24, 2016 Feb 28, 2024 Jan 3, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.689G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Arg230Leu missense NC_000001.11:g.17022684C>A NC_000001.10:g.17349179C>A NG_012340.1:g.36487G>T LRG_316:g.36487G>T LRG_316t1:c.689G>T LRG_316p1:p.Arg230Leu - Protein change
- R230L
- Other names
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- Canonical SPDI
- NC_000001.11:17022683:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SDHB | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
- | 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
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Jul 17, 2023 | RCV000164275.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2024 | RCV000473831.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 7, 2023 | RCV000522081.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 2, 2023 | RCV003474855.1 |
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
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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
(Jun 07, 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: SCV000616874.5
First in ClinVar: Dec 19, 2017 Last updated: Jun 17, 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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 27539324, 25791839, 25371406, 19351833, 23934599, 18382370, 32501622, 30787465, 35668420, 31492822, 32741965, 34906457) (less)
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Pathogenic
(Jul 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026073.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PS4, PP3, PM5_STR, PM2_SUP
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Pathogenic
(Jul 17, 2023)
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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: SCV000214900.8
First in ClinVar: Mar 24, 2015 Last updated: Oct 28, 2023 |
Comment:
The p.R230L pathogenic mutation (also known as c.689G>T), located in coding exon 7 of the SDHB gene, results from a G to T substitution at … (more)
The p.R230L pathogenic mutation (also known as c.689G>T), located in coding exon 7 of the SDHB gene, results from a G to T substitution at nucleotide position 689. The arginine at codon 230 is replaced by leucine, an amino acid with dissimilar properties. This variant has been described in multiple unrelated individuals with extra-adrenal paragangliomas (Neumann HP et al. Cancer Res. 2009 Apr; 69(8):3650-6; Klein RD et al. Diagn. Mol. Pathol. 2008 Jun; 17(2):94-100; Jasperson KW et al. Fam. Cancer. 2013 Aug; Michaowska I et al. Neuroendocrinology. 2015 ; 101(4):321-30; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23). Two other alterations at the same codon, p.R230H (c.689G>A) and p.R230C (c.688C>T), have been detected in numerous individuals diagnosed with pheochromocytomas and/or paragangliomas (Gimenez-Roqueplo AP et al. Cancer Res. 2003 Sep 1;63(17):5615-21; Dahia PL et al. PLoS Genet. 2005 Jul;1(1):72-80; Neumann HP et al. Cancer Res. 2009 Apr 15;69(8):3650-6; Sevilla MA et al. Otolaryngol Head Neck Surg. 2009 May;140(5):724-9; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27; Cerecer-Gil et al. Clin Cancer Res 2010 Aug 15; 16(16):4148-54; Yang C et al. FASEB J. 2012 Nov;26(11):4506-16; Andrews KA et al. J. Med. Genet. 2018 Jun;55:384-394). 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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Likely pathogenic
(May 02, 2023)
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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: SCV004203023.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 03, 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: SCV000554032.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 230 of the SDHB protein (p.Arg230Leu). … (more)
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 230 of the SDHB protein (p.Arg230Leu). This variant is present in population databases (rs587782604, gnomAD 0.0009%). This missense change has been observed in individuals with paraganglioma (PMID: 18382370, 19351833, 23934599, 27539324). ClinVar contains an entry for this variant (Variation ID: 184933). 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: 16912137, 20592014, 25405498, 26259135). 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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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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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 |
Usefulness of Somatostatin Receptor Scintigraphy (Tc-[HYNIC, Tyr3]-Octreotide) and 123I-Metaiodobenzylguanidine Scintigraphy in Patients with SDHx Gene-Related Pheochromocytomas and Paragangliomas Detected by Computed Tomography. | Michałowska I | Neuroendocrinology | 2015 | PMID: 25791839 |
SDHD immunohistochemistry: a new tool to validate SDHx mutations in pheochromocytoma/paraganglioma. | Menara M | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 25405498 |
Role of rapid sequence whole-body MRI screening in SDH-associated hereditary paraganglioma families. | Jasperson KW | Familial cancer | 2014 | PMID: 23934599 |
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 |
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 |
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 |
Text-mined citations for rs587782604 ...
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.