ClinVar Genomic variation as it relates to human health
NM_003001.5(SDHC):c.214C>G (p.Arg72Gly)
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.
Pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003001.5(SDHC):c.214C>G (p.Arg72Gly)
Variation ID: 1786711 Accession: VCV001786711.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q23.3 1: 161340628 (GRCh38) [ NCBI UCSC ] 1: 161310418 (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 Nov 29, 2022 May 1, 2024 Aug 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003001.5:c.214C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002992.1:p.Arg72Gly missense NM_001035511.3:c.214C>G NP_001030588.1:p.Arg72Gly missense NM_001035512.3:c.112C>G NP_001030589.1:p.Arg38Gly missense NM_001035513.3:c.55C>G NP_001030590.1:p.Arg19Gly missense NM_001278172.3:c.112C>G NP_001265101.1:p.Arg38Gly missense NM_001407115.1:c.334C>G NP_001394044.1:p.Arg112Gly missense NM_001407116.1:c.157C>G NP_001394045.1:p.Arg53Gly missense NM_001407117.1:c.157C>G NP_001394046.1:p.Arg53Gly missense NM_001407118.1:c.112C>G NP_001394047.1:p.Arg38Gly missense NM_001407119.1:c.103C>G NP_001394048.1:p.Arg35Gly missense NM_001407120.1:c.103C>G NP_001394049.1:p.Arg35Gly missense NM_001407121.1:c.157C>G NP_001394050.1:p.Arg53Gly missense NR_103459.3:n.266C>G NC_000001.11:g.161340628C>G NC_000001.10:g.161310418C>G NG_012767.1:g.31253C>G LRG_317:g.31253C>G LRG_317t1:c.214C>G LRG_317p1:p.Arg72Gly - Protein change
- R53G, R112G, R35G, R38G, R72G, R19G
- Other names
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- Canonical SPDI
- NC_000001.11:161340627:C:G
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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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- Links
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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SDHC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
860 | 902 |
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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Dec 16, 2020 | RCV002432431.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 28, 2023 | RCV003098662.3 |
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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Uncertain significance
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 3
Gastrointestinal stromal tumor
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: SCV003261008.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 72 of the SDHC protein (p.Arg72Gly). … (more)
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 72 of the SDHC protein (p.Arg72Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SDHC-related conditions (PMID: 24758179). ClinVar contains an entry for this variant (Variation ID: 1786711). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg72 amino acid residue in SDHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17636259, 18212813, 19454582, 24758179, 25950479, 27262318, 27867439; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Dec 16, 2020)
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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: SCV002728027.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R72G pathogenic mutation (also known as c.214C>G), located in coding exon 4 of the SDHC gene, results from a C to G substitution at … (more)
The p.R72G pathogenic mutation (also known as c.214C>G), located in coding exon 4 of the SDHC gene, results from a C to G substitution at nucleotide position 214. The arginine at codon 72 is replaced by glycine, an amino acid with dissimilar properties. This mutation has been reported in a 32-year-old female individual with a norepinephrine-positive head and neck paraganglioma (Else T et al. J. Clin. Endocrinol. Metab., 2014 Aug;99:E1482-6). Another alteration at the same codon, p.R72H (c.215G>A), has been described in multiple individuals with a paraganglioma (Burnichon N et al. J Clin Endocrinol Metab, 2009 Aug;94:2817-27; Buffet A et al. Horm Metab Res, 2012 May;44:359-66; Gupta S et al. Endocr Pathol, 2016 Sep;27:243-52). Based on internal structural analysis, p.R72G disrupts the catalytic function of succinate dehydrogenase, via impacts on quinone binding and/or reduction to quinol (Sun F et al. Cell, 2005 Jul;121:1043-57; Lemarie A et al. Mitochondrion, 2009 Jul;9:254-60; Kluckova K et al. Cell Death Dis, 2015 May;6:e1749). 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)
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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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Evaluation of Head and Neck Paragangliomas by Computed Tomography in Patients with Pheochromocytoma-Paraganglioma Syndromes. | Michałowska I | Polish journal of radiology | 2016 | PMID: 27867439 |
Urinary Bladder Paragangliomas: Analysis of Succinate Dehydrogenase and Outcome. | Gupta S | Endocrine pathology | 2016 | PMID: 27262318 |
Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation. | Kluckova K | Cell death & disease | 2015 | PMID: 25950479 |
The clinical phenotype of SDHC-associated hereditary paraganglioma syndrome (PGL3). | Else T | The Journal of clinical endocrinology and metabolism | 2014 | PMID: 24758179 |
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 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 |
Mutations in the heme b-binding residue of SDHC inhibit assembly of respiratory chain complex II in mammalian cells. | Lemarie A | Mitochondrion | 2009 | PMID: 19332149 |
Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. | Peczkowska M | Nature clinical practice. Endocrinology & metabolism | 2008 | PMID: 18212813 |
Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate. | Szeto SSW | The Journal of biological chemistry | 2007 | PMID: 17636259 |
Crystal structure of mitochondrial respiratory membrane protein complex II. | Sun F | Cell | 2005 | PMID: 15989954 |
Text-mined citations for this variant ...
HelpRecord last updated Sep 01, 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.