ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.640C>T (p.Gln214Ter)
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
-
NM_003000.3(SDHB):c.640C>T (p.Gln214Ter)
Variation ID: 230243 Accession: VCV000230243.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p36.13 1: 17023975 (GRCh38) [ NCBI UCSC ] 1: 17350470 (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 May 29, 2016 Apr 20, 2024 Nov 2, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_003000.3:c.640C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Gln214Ter nonsense NC_000001.11:g.17023975G>A NC_000001.10:g.17350470G>A NG_012340.1:g.35196C>T LRG_316:g.35196C>T LRG_316t1:c.640C>T LRG_316p1:p.Gln214Ter - Protein change
- Q214*
- Other names
- -
- Canonical SPDI
- NC_000001.11:17023974:G:A
-
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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 |
1271 | 1385 |
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
|
Jul 27, 2022 | RCV000215175.3 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 15, 2023 | RCV000238597.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 5, 2023 | RCV000472972.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
Feb 27, 2023 | RCV000657586.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000762866.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 2, 2023 | RCV001175589.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 5, 2022 | RCV003475004.1 |
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. |
|
---|---|---|---|---|---|
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: SCV000893246.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(Mar 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary Paraganglioma-Pheochromocytoma Syndromes
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001339227.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: SDHB c.640C>T (p.Gln214X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: SDHB c.640C>T (p.Gln214X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant was absent in 251290 control chromosomes. c.640C>T has been reported in the literature in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (Reusch_2007, Kim_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Likely pathogenic
(Aug 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Paragangliomas 4
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
maternal
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001480232.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Comment:
The inherited c.640C>T (p.Gln214Ter) variant identified in the SDHB gene leads to the premature termination of the protein at amino acid 214/281 (coding exon 6/8) … (more)
The inherited c.640C>T (p.Gln214Ter) variant identified in the SDHB gene leads to the premature termination of the protein at amino acid 214/281 (coding exon 6/8) and is predicted to undergo nonsense mediated decay. This variant is absent from gnomAD and ExAC, suggesting it is not a common benign variant in the populations represented in these databases. This variant is classified as Pathogenic in ClinVar (VarID:230243), and has been reported in the literature in individuals with early onset Pheochromocytomas [PMID: 17943698; PMID: 19694205]. Given its deleterious nature, its absence in population databases, and its observation in affected individuals in the literature, the c.640C>T (p.Gln214Ter) variant identified in the SDHB gene is reported here as Likely Pathogenic. (less)
Clinical Features:
Seizure (present)
Secondary finding: yes
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Paragangliomas 4
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002059106.2
First in ClinVar: Jan 15, 2022 Last updated: Apr 08, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000230243, PMID:17943698). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Paraganglioma (present)
|
|
Pathogenic
(Jul 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000273710.7
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.Q214* pathogenic mutation (also known as c.640C>T) located in coding exon 6 of the SDHB gene, results from a C to T substitution at … (more)
The p.Q214* pathogenic mutation (also known as c.640C>T) located in coding exon 6 of the SDHB gene, results from a C to T substitution at nucleotide position 640. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This mutation was first described in a 40-year-old Chinese female with a recurrent pheochromocytoma in the left adrenal gland. The patient's first pheochromocytoma had been removed 18 years prior to this study (Reusch J et al. Exp Clin Endocrinol Diabetes. 2007;115(9):616-8). It was also identified in a 15 year-old female with hypertension due to a functional abdominal paraganglioma (Kim MS et al. J. Pediatr. Endocrinol. Metab. 2009 Jun; 22(6):565-71). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Oct 13, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Paragangliomas 4
Affected status: unknown
Allele origin:
unknown
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000297132.3
First in ClinVar: Jul 31, 2016 Last updated: Dec 24, 2022 |
|
|
Pathogenic
(Feb 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000779323.3
First in ClinVar: Jul 09, 2018 Last updated: Mar 18, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19694205, 25525159, 17943698, 28873162, 30787465) (less)
|
|
Pathogenic
(Mar 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Paragangliomas 4
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018201.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
|
|
Likely pathogenic
(Jun 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Gastrointestinal stromal tumor
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004203038.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jan 05, 2023)
|
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
|
Invitae
Accession: SCV000554012.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal is associated with altered splicing resulting … (more)
For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 230243). This premature translational stop signal has been observed in individual(s) with pheochromocytoma and paraganglioma (PMID: 17943698, 19694205). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln214*) in the SDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). (less)
|
|
Pathogenic
(Nov 02, 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: SCV004821939.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This variant changes 1 nucleotide in exon 6 of the SDHB gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 6 of the SDHB gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hereditary paranganglioma-pheochromocytoma syndrome (PMID: 17943698, 19694205, 32460727, 34654328). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHB function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Head and Neck Malignant Paragangliomas: Experience from a Single Institution. | Ding Y | Ear, nose, & throat journal | 2021 | PMID: 34654328 |
Identification of a novel SDHB c.563 T > C mutation responsible for Paraganglioma syndrome and genetic analysis of the SDHB gene in China: a case report. | Chen H | BMC medical genetics | 2020 | PMID: 32460727 |
Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. | Ricketts CJ | Human mutation | 2010 | PMID: 19802898 |
Ischemic stroke and rhabdomyolysis in a 15-year-old girl with paraganglioma due to an SDHB exon 6 (Q214X) mutation. | Kim MS | Journal of pediatric endocrinology & metabolism : JPEM | 2009 | PMID: 19694205 |
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 |
Relapsing pheochromocytoma in a Chinese women caused by a novel mutation in exon 6 of the SDHB gene: a case report. | Reusch J | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2007 | PMID: 17943698 |
Text-mined citations for rs876658461 ...
HelpRecord last updated Apr 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.