ClinVar Genomic variation as it relates to human health
NM_003000.3(SDHB):c.724C>T (p.Arg242Cys)
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>T (p.Arg242Cys)
Variation ID: 186827 Accession: VCV000186827.34
- 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 Jun 30, 2017 Apr 15, 2024 Dec 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003000.3:c.724C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002991.2:p.Arg242Cys missense NC_000001.11:g.17022649G>A NC_000001.10:g.17349144G>A NG_012340.1:g.36522C>T LRG_316:g.36522C>T LRG_316t1:c.724C>T LRG_316p1:p.Arg242Cys - Protein change
- R242C
- Other names
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- Canonical SPDI
- NC_000001.11:17022648:G:A
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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 |
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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 2, 2019 | RCV000166478.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 29, 2023 | RCV000461517.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 15, 2022 | RCV001092589.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 23, 2023 | RCV003474878.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 18, 2023 | RCV003316054.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV003937515.1 |
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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Pathogenic
(Jan 02, 2019)
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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: SCV000217276.7
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The p.R242C pathogenic mutation (also known as c.724C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at … (more)
The p.R242C pathogenic mutation (also known as c.724C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 724. The arginine at codon 242 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in numerous individuals with sporadic and familial paragangliomas/pheochromocytomas (Jafri M et al. Clin. Endocrinol. (Oxf). 2013 Jun;78(6):898-906; Lefebvre S et al. Horm. Metab. Res. 2012 May;44(5):334-8; Badenhop RF et al. J. Med. Genet. 2004 Jul;41(7):e99; Schiavi F et al. Ann. N. Y. Acad. Sci. 2006 Aug;1073:190-7; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug; 94(8):2817-27; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394). A functional study utilizing a yeast growth assay classified this alteration as a "mildly impaired mutation" after finding that analogous yeast p.R242C mutants were able to partially rescue oxidative cell growth but had significantly decreased SDH enzyme activity (Panizza E et al. Hum. Mol. Genet. 2013 Feb; 22(4):804-15). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 15, 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: SCV002574292.2
First in ClinVar: Sep 24, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate intermediate SDH activity (Panizza et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Published functional studies demonstrate intermediate SDH activity (Panizza et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24606901, 26464466, 33087929, 22517554, 15235042, 30217213, 29386252, 23072324, 17102086, 19802898, 19351833, 19454582, 23175444) (less)
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Likely pathogenic
(Apr 18, 2023)
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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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Myriad Genetics, Inc.
Accession: SCV004018067.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:19454582, 31194233, 17102086, 32035780, 30201732]. … (more)
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:19454582, 31194233, 17102086, 32035780, 30201732]. Functional studies indicate this variant impacts protein function [PMID: 26719882]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(Jun 23, 2023)
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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: SCV004203010.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 29, 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: SCV000554036.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This missense change has been observed in individuals with hereditary paraganglioma or pheochromocytoma (PMID: 15235042, 17102086, 19351833, 19802898, 22517554). This sequence change replaces arginine, which … (more)
This missense change has been observed in individuals with hereditary paraganglioma or pheochromocytoma (PMID: 15235042, 17102086, 19351833, 19802898, 22517554). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 242 of the SDHB protein (p.Arg242Cys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 186827). 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. 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: 12000816, 19351833, 20208144). 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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Pathogenic
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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SDHB-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004748095.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The SDHB c.724C>T variant is predicted to result in the amino acid substitution p.Arg242Cys. This variant has been reported in multiple individuals with pheochromocytoma or … (more)
The SDHB c.724C>T variant is predicted to result in the amino acid substitution p.Arg242Cys. This variant has been reported in multiple individuals with pheochromocytoma or paraganglioma (Lefebvre et al. 2012. PubMed ID: 22517554; Table S2, Garrett et al. 2022. PubMed ID: 34906457; Kim et al. 2022. PubMed ID: 33219105). Functional studies in yeast found this variant has a mild impact on SDHB function (Panizza et al. 2013. PubMed ID: 23175444). This variant has not been reported in a large population database, indicating this variant is rare. Additionally, different missense variants (p.Arg242His, p.Arg242Ser) affecting this amino acid have been documented as pathogenic (Table S2, Garrett et al. 2022. PubMed ID: 34906457). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 01, 2016)
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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: SCV001249150.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
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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Tumor-specific prognosis of mutation-positive patients with head and neck paragangliomas. | Sen I | Journal of vascular surgery | 2020 | PMID: 32035780 |
Characterization of Malignant Head and Neck Paragangliomas at a Single Institution Across Multiple Decades. | McCrary HC | JAMA otolaryngology-- head & neck surgery | 2019 | PMID: 31194233 |
Secondary findings in 421 whole exome-sequenced Chinese children. | Chen W | Human genomics | 2018 | PMID: 30217213 |
Bayesian approach to determining penetrance of pathogenic SDH variants. | Benn DE | Journal of medical genetics | 2018 | PMID: 30201732 |
Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. | Andrews KA | Journal of medical genetics | 2018 | PMID: 29386252 |
SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. | Saxena N | Journal of the National Cancer Institute | 2016 | PMID: 26719882 |
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 |
Evaluation of SDHB, SDHD and VHL gene susceptibility testing in the assessment of individuals with non-syndromic phaeochromocytoma, paraganglioma and head and neck paraganglioma. | Jafri M | Clinical endocrinology | 2013 | PMID: 23072324 |
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 |
Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management. | Hermsen MA | Cellular oncology : the official journal of the International Society for Cellular Oncology | 2010 | PMID: 20208144 |
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 |
Sequence variation in human succinate dehydrogenase genes: evidence for long-term balancing selection on SDHA. | Baysal BE | BMC biology | 2007 | PMID: 17376234 |
Paraganglioma syndrome: SDHB, SDHC, and SDHD mutations in head and neck paragangliomas. | Schiavi F | Annals of the New York Academy of Sciences | 2006 | PMID: 17102086 |
The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features. | Badenhop RF | Journal of medical genetics | 2004 | PMID: 15235042 |
Germ-line mutations in nonsyndromic pheochromocytoma. | Neumann HP | The New England journal of medicine | 2002 | PMID: 12000816 |
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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.