ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.724C>A (p.Arg242Ser)
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.724C>A (p.Arg242Ser)
Variation ID: 239443 Accession: VCV000239443.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 17022649 (GRCh38) [ NCBI UCSC ] 1: 17349144 (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 19, 2017 Feb 28, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.724C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Arg242Ser missense NC_000001.11:g.17022649G>T NC_000001.10:g.17349144G>T NG_012340.1:g.36522C>A LRG_316:g.36522C>A LRG_316t1:c.724C>A LRG_316p1:p.Arg242Ser - Protein change
- R242S
- Other names
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- Canonical SPDI
- NC_000001.11:17022648:G: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 |
1291 | 1406 |
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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Jan 30, 2024 | RCV000226466.11 | |
Pathogenic (1) |
criteria provided, single submitter
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May 25, 2017 | RCV000523546.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 17, 2021 | RCV000492633.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 17, 2023 | RCV003323466.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2023 | RCV003514330.1 |
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
(May 25, 2017)
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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: SCV000616875.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
This pathogenic variant is denoted SDHB c.724C>A at the cDNA level, p.Arg242Ser (R242S) at theprotein level, and results in the change of an Arginine to … (more)
This pathogenic variant is denoted SDHB c.724C>A at the cDNA level, p.Arg242Ser (R242S) at theprotein level, and results in the change of an Arginine to a Serine (CGC>AGC). This variant has been reported in atleast two individuals with head and neck paraganglioma (Neumann 2009). Functional assays in yeast demonstratedthat this variant affects SDH enzyme activity and increases mtDNA mutability and sensitivity to oxidative stress(Panizza 2013). SDHB Arg242Ser was not observed in large population cohorts (NHLBI Exome Sequencing Project,The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Serine differ in some properties, this isconsidered a semi-conservative amino acid substitution. SDHB Arg242Ser occurs at a position that is conservedacross species and is located in the second L(I)YR motif (Maio 2014, Saxena 2015). In silico analyses predict that thispathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, weconsider this variant to be pathogenic (less)
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Pathogenic
(Mar 17, 2021)
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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: SCV000581213.5
First in ClinVar: Jul 01, 2017 Last updated: Nov 29, 2022 |
Comment:
The p.R242S pathogenic mutation (also known as c.724C>A), located in coding exon 7 of the SDHB gene, results from a C to A substitution at … (more)
The p.R242S pathogenic mutation (also known as c.724C>A), located in coding exon 7 of the SDHB gene, results from a C to A substitution at nucleotide position 724. The arginine at codon 242 is replaced by serine, an amino acid with dissimilar properties. This alteration was reported in 2/578 individuals with head and neck paragangliomas (Neumann HP et al. Cancer Res. 2009 Apr;69(8):3650-6). In addition, a different disease causing mutation, p.R242H, has been described at this position (Kim E et al. Endocr. Relat. Cancer. 2015 Jun; 22(3):387-97). Functional studies using yeast models determined that the yeast-equivalent alteration of p.R242S, yR235S, results in an OXPHOS phenotype similar to the null strain; with no detectable SDH activity, 50% reduction in respiration, and increased genomic instability (Panizza E et al. Hum. Mol. Genet. 2013 Feb;22(4):804-15). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 available evidence, this alteration is classified as a pathogenic mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 17, 2023)
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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: SCV004029460.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: SDHB c.724C>A (p.Arg242Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: SDHB c.724C>A (p.Arg242Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes. c.724C>A has been reported in the literature in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (e.g. Neumann_2009, Siddiqui_2021, Garrett_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in undetectable SDH enzyme activity in vitro (e.g. Panizza_2013). The following publications have been ascertained in the context of this evaluation (PMID: 34906457, 19351833, 23175444, 34377882). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 01, 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: SCV004362268.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with serine at codon 242 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with serine at codon 242 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 in yeast have shown that this variant signifiantly affected SDH activity and mitochondrial respiration, increasing of mtDNA mutability and sensitivity to oxidative stress. The variant disrupts a functionally important LYR motif. (PMID: 23175444, 26719882). This variant has been reported in individuals affected with paragangliomas and/or pheochromocytomas (PMID: 19351833, 34377882, 34906457, 35870552). Other variants at this position are considered disease causing (ClinVar Variation ID: VCV000012781, VCV000186827). 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
(Jan 30, 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: SCV000287789.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 242 of the SDHB protein (p.Arg242Ser). … (more)
This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 242 of the SDHB protein (p.Arg242Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma (PMID: 19351833; Invitae). ClinVar contains an entry for this variant (Variation ID: 239443). 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 not expected to disrupt SDHB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 23175444). This variant disrupts the p.Arg242 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19351833, 21173220, 22517554). 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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Serum fatty acid profiling in patients with SDHx mutations: New advances on cellular metabolism in SDH deficiency. | Vamecq J | Biochimie | 2022 | PMID: 35870552 |
Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD. | Garrett A | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906457 |
SDHB-Associated Paraganglioma Syndrome in Africa-A Need for Greater Genetic Testing. | Siddiqui N | Journal of the Endocrine Society | 2021 | PMID: 34377882 |
SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. | Saxena N | Journal of the National Cancer Institute | 2016 | PMID: 26719882 |
Structural and functional consequences of succinate dehydrogenase subunit B mutations. | Kim E | Endocrine-related cancer | 2015 | PMID: 25972245 |
Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. | Panizza E | Human molecular genetics | 2013 | PMID: 23175444 |
Screening of mutations in genes that predispose to hereditary paragangliomas and pheochromocytomas. | Lefebvre S | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2012 | PMID: 22517554 |
Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. | Janeway KA | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 21173220 |
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 |
Text-mined citations for rs786203251 ...
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.