ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.541-2A>G
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.541-2A>G
Variation ID: 183925 Accession: VCV000183925.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17024076 (GRCh38) [ NCBI UCSC ] 1: 17350571 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Feb 28, 2024 Jan 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.541-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001407361.1:c.487-2A>G splice acceptor NC_000001.11:g.17024076T>C NC_000001.10:g.17350571T>C NG_012340.1:g.35095A>G LRG_316:g.35095A>G LRG_316t1:c.541-2A>G - Protein change
- Other names
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- Canonical SPDI
- NC_000001.11:17024075:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SDHB | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1271 | 1385 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Nov 7, 2022 | RCV000162804.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000374774.6 | |
Pathogenic (2) |
criteria provided, single submitter
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Dec 7, 2021 | RCV000505364.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2022 | RCV000523104.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 20, 2024 | RCV000797086.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 25, 2022 | RCV003474848.1 |
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
(Dec 07, 2021)
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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: SCV002050812.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: SDHB c.541-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: SDHB c.541-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249478 control chromosomes. c.541-2A>G has been reported in the literature in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome with reduced penetrance (e.g. Timmers_2007, Neumann_2009, Jochmanova_2017). Four 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
(Nov 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000213285.8
First in ClinVar: Mar 24, 2015 Last updated: Apr 15, 2023 |
Comment:
The c.541-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the SDHB gene. This mutation … (more)
The c.541-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the SDHB gene. This mutation was detected in several individuals with personal and/or family history of pheochromocytoma, paraganglioma, and renal cell carcinoma (Ambry internal data; Timmers HJ et al. J Clin Endocrinol Metab. 2007;92(3):779-86. Ricketts CJ et al. J Urol. 2012 Dec;188(6):2063-71. Choat H, et al. Case Rep Endocrinol 2014 ; 2014:502734; Casey RT et al. J. Clin. Endocrinol. Metab., 2017 11;102:4013-4022; Huang Y et al. Endocr Connect, 2018 Dec;7:1217-1225). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(Dec 21, 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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GeneDx
Accession: SCV000616872.3
First in ClinVar: Dec 19, 2017 Last updated: May 06, 2023 |
Comment:
Canonical splice site variant predicted to result in an in-frame deletion of a critical region, including the 4FE-4S ferredoxin-type domain and Iron-sulfur 2 (4Fe-4S), Iron-sulfur … (more)
Canonical splice site variant predicted to result in an in-frame deletion of a critical region, including the 4FE-4S ferredoxin-type domain and Iron-sulfur 2 (4Fe-4S), Iron-sulfur 3 (3Fe-4S), and ubiquinone binding sites (UniProt); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23083876, 25525159, 25298897, 28748451, 25873086, 17200167, 28374168, 27159321, 28973655, 30352407, 19351833, 26642834, 29504908, 25371406, 31705439, 31579262, 32124427, 31492822, 27535533, 34703596) (less)
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Pathogenic
(Apr 25, 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: SCV004203039.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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SDHB-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000351417.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The c.541-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The variant has … (more)
The c.541-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in three studies in which it is found in a total of four hereditary paraganglioma-pheochromocytoma syndrome patients, all in a heterozygous state (Timmers et al. 2007; Ricketts et al. 2012; Choat et al. 2014). The variant was absent from an unaffected brother of one of the patients (Choat et al. 2014). Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Based on the evidence and the potential impact of splice acceptor variants, the c.541-2A>G variant is classified as likely pathogenic for SDHB-related disorders. (less)
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Pathogenic
(Jan 20, 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: SCV000936626.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 5 of the SDHB gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 5 of the SDHB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with leukodystrophic encephalopathy and paragangliomas and pheochromocytomas (PMID: 17200167, 23083876, 25298897, 26642834). This variant is also known as IVS5–2A>G. ClinVar contains an entry for this variant (Variation ID: 183925). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV000599511.1
First in ClinVar: Sep 15, 2017 Last updated: Sep 15, 2017 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients. | Huang Y | Endocrine connections | 2018 | PMID: 30352407 |
Clinical and Molecular Features of Renal and Pheochromocytoma/Paraganglioma Tumor Association Syndrome (RAPTAS): Case Series and Literature Review. | Casey RT | The Journal of clinical endocrinology and metabolism | 2017 | PMID: 28973655 |
SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations. | Jochmanova I | Journal of cancer research and clinical oncology | 2017 | PMID: 28374168 |
Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy. | Helman G | Annals of neurology | 2016 | PMID: 26642834 |
SDHB-Associated Paraganglioma in a Pediatric Patient and Literature Review on Hereditary Pheochromocytoma-Paraganglioma Syndromes. | Choat H | Case reports in endocrinology | 2014 | PMID: 25298897 |
Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. | Ricketts CJ | The Journal of urology | 2012 | PMID: 23083876 |
Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. | Ricketts CJ | Human mutation | 2010 | PMID: 19802898 |
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 |
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 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
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Text-mined citations for rs786201161 ...
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.