ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.423+20T>A
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.
Uncertain significance(2); Benign(5); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003000.3(SDHB):c.423+20T>A
Variation ID: 36769 Accession: VCV000036769.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17028580 (GRCh38) [ NCBI UCSC ] 1: 17355075 (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 Jul 1, 2016 Aug 4, 2024 Jul 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.423+20T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000001.11:g.17028580A>T NC_000001.10:g.17355075A>T NG_012340.1:g.30591T>A LRG_316:g.30591T>A LRG_316t1:c.423+20T>A - Protein change
- Other names
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- Canonical SPDI
- NC_000001.11:17028579:A: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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0.00120 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00094
1000 Genomes Project 0.00120
Trans-Omics for Precision Medicine (TOPMed) 0.00174
The Genome Aggregation Database (gnomAD) 0.00179
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00215
Exome Aggregation Consortium (ExAC) 0.00308
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
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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
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 |
1324 | 1442 |
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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Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000183209.29 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV000204733.12 | |
Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2024 | RCV000514661.33 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 21, 2018 | RCV000755700.10 | |
Likely benign (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000986264.9 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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May 29, 2020 | RCV002257364.11 |
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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Benign
(May 29, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002527074.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Aug 06, 2015)
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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: SCV002632090.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.423+20T>A intronic variant results from a T to A substitution 20 nucleotides after coding exon 4 in the SDHB gene. In one study, this … (more)
The c.423+20T>A intronic variant results from a T to A substitution 20 nucleotides after coding exon 4 in the SDHB gene. In one study, this alteration was reported in 2 apparently unrelated individuals with an adrenal pheochromocytoma diagnosed prior to age 50 (Srirangalingam U et al. Clin Endocrinol. 2008 Oct;69(4):587-96). Neither of these probands had an identifiable VHL mutation; however, other susceptibility genes were not assessed. Authors classified c.423+20T>A as a mutation, but cautioned that further studies were needed to confirm pathogenicity. This variant was previously reported in the SNPDatabase as rs190139590. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.22% (28/13006), having been observed in 0.02% (1/4406) of African American alleles, and in 0.31% (27/8600) of European American alleles studied. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 0.05% (1/2184). The highest observed frequency was 1 of 178 (0.56%) British chromosomes studied. To date, this alteration has been detected with an allele frequency of approximately 0.03% (greater than 6100 alleles tested) in our clinical cohort. Based on nucleotide sequence alignment, this position is poorly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a cryptic splice acceptor site in close proximity to the native donor site; however, direct evidence is unavailable. Since supporting evidence for this variant is conflicting at this time, the clinical significance of c.423+20T>A remains unclear. (less)
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Benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000309330.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Likely benign
(Jul 07, 2017)
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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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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610707.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
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Likely benign
(Jun 29, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000235628.13
First in ClinVar: Jul 05, 2015 Last updated: Oct 09, 2016 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Uncertain significance
(Nov 21, 2018)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
Affected status: unknown
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000883133.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
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Benign
(Sep 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001158675.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 08, 2022 |
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Benign
(Jun 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053117.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 11, 2022 |
Comment:
Variant summary: The SDHB c.423+20T>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. … (more)
Variant summary: The SDHB c.423+20T>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and 4/5 splice prediction tools predict changes of a cryptic splicing site. ESEfinder predicts changes of RNA splicing enhancer sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 374/121320 control chromosomes (4 homozygotes) at a frequency of 0.0030828, which is approximately 3523 times the estimated maximal expected allele frequency of a pathogenic SDHB variant (0.0000009), suggesting this variant is likely a benign polymorphism. This variant has been reported in the affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. (less)
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Likely benign
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552174.4
First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023 |
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Likely benign
(Jul 01, 2024)
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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: SCV002543876.14
First in ClinVar: Jul 09, 2022 Last updated: Aug 04, 2024 |
Comment:
SDHB: BS2
Number of individuals with the variant: 33
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Likely benign
(Feb 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540302.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been classified in HGMD as DM. It has been seen in 2 patients with pheochromocytomas and one with GIST. It is present with a MaxMAF of 0.89% in ExAC (high for disease frequency - 0.8/100,000 person-years). It is classified in ClinVar with 1 star as benign/likely benign by Invitae, GeneDx, Prevention genetics and as likely path by LabCorp (in 2011). (less)
Method: Genome/Exome Filtration
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Likely benign
(May 28, 2019)
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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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Mendelics
Accession: SCV001135203.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Benign
(Feb 01, 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: SCV000262420.5
First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550911.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The SDHB c.423+20T>A variant was identified in the in heterozygous state in the tumour of one patient with pheochromocytoma (Pantaleo_2014_23612575) and in the tumours of … (more)
The SDHB c.423+20T>A variant was identified in the in heterozygous state in the tumour of one patient with pheochromocytoma (Pantaleo_2014_23612575) and in the tumours of two patients with Carney Triad (association of paragangliomas, pulmonary chondromas, and gastrointestinal stromal tumors with variety of other lesions including pheochromocytomas and adrenocortical tumors) who were also found to have SDHD c.388insG variants (Szarek_2015_25808178). The variant was also identified in dbSNP (ID: rs190139590) as ‚ÄúWith Likely pathogenic allele‚Äù. The variant was found in ClinVar with conflicting interpretations of pathogenicity as it was classified as likely benign by Children's Mercy Hospital and Clinics, GeneDx, and Laboratory for Molecular Medicine at Partners HealthCare Personalized Medicine, benign by Prevention Genetics and Invitae, but was classified as likely pathogenic by Integrated Genetics/Laboratory Corporation of America. The variant was found in LOVD 3.0 where it was reported as likely benign. The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 847 of 282734 chromosomes (8 homozygous) at a frequency of 0.002996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 295 of 30614 chromosomes (freq: 0.009636), Ashkenazi Jewish in 69 of 10370 chromosomes (freq: 0.006654), Other in 28 of 7224 chromosomes (freq: 0.003876), European (Non-Finnish) in 370 of 129148 chromosomes (freq: 0.002865), Latino in 71 of 35438 chromosomes (freq: 0.002003), European (Finnish) in 10 of 25020 chromosomes (freq: 0.0004), African in 3 of 24966 chromosomes (freq: 0.00012) and East African in 1 of 19954 chromosomes (freq: 0.00005). Pathogenic variants in SDHB have been associated with Cowden Syndrome, an autosomal dominant condition with an estimated prevalence of 1 in 200 000 and Paragangliomas, an autosomal dominant condition with an estimated prevalence of 1 in 1 000 000. The observed allele frequency is therefore higher than would be expected for the disorder. Three in silico splicing programs (SpliceSiteFinder-like, MaxEntScan, NNSPLICE) predict a greater than 10% change in splicing which would lead to the creation of a new 3' splice site, however MutationTaster predicts that this variant is a polymorphism. This information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Pantaleo, Maria A., et al. "Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST." European Journal of Human Genetics 22.1 (2014): 32. Szarek, Eva, et al. "Carney triad, SDH-deficient tumors, and Sdhb+/‚à à mice share abnormal mitochondria." Endocrine-related cancer 22.3 (2015): 345-352. (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808242.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926753.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952149.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST. | Pantaleo MA | European journal of human genetics : EJHG | 2014 | PMID: 23612575 |
Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers. | Srirangalingam U | Clinical endocrinology | 2008 | PMID: 18419787 |
Text-mined citations for rs190139590 ...
HelpRecord last updated Sep 08, 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.