ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.758G>A (p.Cys253Tyr)
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.758G>A (p.Cys253Tyr)
Variation ID: 183795 Accession: VCV000183795.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17022615 (GRCh38) [ NCBI UCSC ] 1: 17349110 (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 Apr 20, 2024 Aug 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.758G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Cys253Tyr missense NC_000001.11:g.17022615C>T NC_000001.10:g.17349110C>T NG_012340.1:g.36556G>A LRG_316:g.36556G>A LRG_316t1:c.758G>A LRG_316p1:p.Cys253Tyr - Protein change
- C253Y
- Other names
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- Canonical SPDI
- NC_000001.11:17022614: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
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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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Jun 21, 2018 | RCV000162580.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 4, 2023 | RCV001040032.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 16, 2023 | RCV003514319.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 15, 2023 | RCV003995206.1 |
Submissions - Germline
Classification
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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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Likely pathogenic
(Jun 21, 2018)
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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: SCV000212996.7
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The p.C253Y variant (also known as c.758G>A) is located in coding exon 7 of the SDHB gene. This alteration results from a G to A … (more)
The p.C253Y variant (also known as c.758G>A) is located in coding exon 7 of the SDHB gene. This alteration results from a G to A substitution at nucleotide position 758. The cysteine at codon 253 is replaced by tyrosine, an amino acid with highly dissimilar properties. Multiple studies have identified this alteration in patients with pheochromocytomas and/or paragangliomas, often with apparently sporadic presentation (Amar L et al. J. Clin Oncol 2005 Dec 1;23(34):8812-8, Amar L et al. J. Clin. Endocrinol. Metab. 2007 Oct; 92(10):3822-8, Favier J et al. PLoS ONE 2009;4(9):e7094, Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug; 94(8):2817-27; Patócs A et al. Pathol. Oncol. Res. 2016 Oct;22(4):673-9). Based on protein sequence alignment, this amino acid position is highly conserved and located in a highly conserved region of the protein. The Cys253 residue plays a vital role coordinating the Fe4S4 cluster, and it is believed that alterations at this location would prevent assembly of Complex II (Iverson TM et al. J. Biol. Chem. 2012 Oct; 287(42):35430-8). In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 4
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004362267.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces cysteine with tyrosine at codon 253 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces cysteine with tyrosine at codon 253 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant abolished both the succinate co-Q oxidoreductase (SQR) activity and succinate dehydrogenase (SDH) activity of mitochondrial complex II, and impaired SDHB association with SDHA and the formation of the full SDH complex (CII; PMID: 26719882). This variant has been reported in numerous individuals affected with paraganglioma and pheochromocytoma in the literature (PMID: 16314641, 17652212, 19454582, 19763184, 22517557,26960314, 34439371). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Aug 04, 2023)
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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: SCV001203587.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
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) … (more)
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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 183795). This missense change has been observed in individuals with paraganglioma-pheochromocytoma syndrome (PMID: 17652212, 19454582, 19763184, 26960314). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 253 of the SDHB protein (p.Cys253Tyr). (less)
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Pathogenic
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004825235.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces cysteine with tyrosine at codon 253 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces cysteine with tyrosine at codon 253 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant abolished both the succinate co-Q oxidoreductase (SQR) activity and succinate dehydrogenase (SDH) activity of mitochondrial complex II, and impaired SDHB association with SDHA and the formation of the full SDH complex (CII; PMID: 26719882). This variant has been reported in numerous individuals affected with paraganglioma and pheochromocytoma in the literature (PMID: 16314641, 17652212, 19454582, 19763184, 22517557,26960314, 34439371). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
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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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Analytical Performance of NGS-Based Molecular Genetic Tests Used in the Diagnostic Workflow of Pheochromocytoma/Paraganglioma. | Sarkadi B | Cancers | 2021 | PMID: 34439371 |
Novel SDHB and TMEM127 Mutations in Patients with Pheochromocytoma/Paraganglioma Syndrome. | Patócs A | Pathology oncology research : POR | 2016 | PMID: 26960314 |
SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. | Saxena N | Journal of the National Cancer Institute | 2016 | PMID: 26719882 |
A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. | Buffet A | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2012 | PMID: 22517557 |
The Warburg effect is genetically determined in inherited pheochromocytomas. | Favier J | PloS one | 2009 | PMID: 19763184 |
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 |
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 |
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 |
Text-mined citations for rs786201085 ...
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.