ClinVar Genomic variation as it relates to human health
NM_003002.4(SDHD):c.64C>T (p.Arg22Ter)
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_003002.4(SDHD):c.64C>T (p.Arg22Ter)
Variation ID: 6903 Accession: VCV000006903.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.1 11: 112087868 (GRCh38) [ NCBI UCSC ] 11: 111958592 (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 Oct 5, 2015 Feb 28, 2024 Oct 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003002.4:c.64C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002993.1:p.Arg22Ter nonsense NM_001276503.2:c.64C>T NP_001263432.1:p.Arg22Ter nonsense NM_001276504.2:c.52+909C>T intron variant NM_001276506.2:c.64C>T NP_001263435.1:p.Arg22Ter nonsense NR_077060.2:n.99C>T non-coding transcript variant NC_000011.10:g.112087868C>T NC_000011.9:g.111958592C>T NG_012337.3:g.6022C>T NG_033145.1:g.3931G>A LRG_9:g.6022C>T LRG_9t1:c.64C>T LRG_9p1:p.Arg22Ter - Protein change
- R22*
- Other names
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- Canonical SPDI
- NC_000011.10:112087867: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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SDHD | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
642 | 778 |
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 (2) |
criteria provided, single submitter
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Apr 21, 2022 | RCV000007312.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 23, 2014 | RCV000193132.13 | |
Pathogenic (1) |
criteria provided, single submitter
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May 20, 2019 | RCV000492341.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2017 | RCV000657641.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV002228006.13 |
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
(Jan 23, 2014)
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criteria provided, single submitter
Method: clinical testing
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Pheochromocytoma
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000248840.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Feb 22, 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: SCV000779386.2
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
Comment:
This variant is denoted SDHD c.64C>T at the cDNA level and p.Arg22Ter (R22X) at the protein level. The substitution creates a nonsense variant, which changes … (more)
This variant is denoted SDHD c.64C>T at the cDNA level and p.Arg22Ter (R22X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple individuals and families with hereditary paraganglioma/pheochromocytoma (Gimenez-Roqueplo 2001, Taschner 2001, Amar 2005, Lefebvre 2012, Piccini 2012) and is considered pathogenic. (less)
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Pathogenic
(May 20, 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: SCV000581232.5
First in ClinVar: Jul 01, 2017 Last updated: Nov 29, 2022 |
Comment:
The p.R22* pathogenic mutation (also known as c.64C>T), located in coding exon 2 of the SDHD gene, results from a C to T substitution at … (more)
The p.R22* pathogenic mutation (also known as c.64C>T), located in coding exon 2 of the SDHD gene, results from a C to T substitution at nucleotide position 64. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been reported in numerous individuals with a personal and/or family history of paraganglioma and/or pheochromocytoma (PGL-PCC) (Amar L et al. J. Clin. Oncol. 2005 Dec; 23(34):8812-8; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar; 91(3):827-36; Piccini V et al. Endocr. Relat. Cancer. 2012 Apr; 19(2):149-55; Cascón A et al. J. Clin. Endocrinol. Metab. 2009 May; 94(5):1701-5; Taschner PE et al. Genes Chromosomes Cancer. 2001 Jul; 31(3):274-81; Andrews KA et al. J. Med. Genet. 2018 Jun;55:384-394). A study including somatic and germline DNA analyses, cosegregation analyses, enzyme function studies and gene expression studies concluded that this mutation is associated with a complete loss of mitochondrial complex II activity and a high expression of angiogenic factors (Gimenez-Roqueplo AP et al. Am. J. Hum. Genet. 2001 Dec; 69(6):1186-97). 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
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Pathogenic
(Apr 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175666.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
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Pathogenic
(Oct 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Carney-Stratakis syndrome
Paragangliomas with sensorineural hearing loss Pheochromocytoma Cowden syndrome 3
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: SCV000762666.7
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg22*) in the SDHD gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg22*) in the SDHD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with paraganglioma and/or pheochromocytoma (PMID: 11391798, 11605159, 16317055, 19258401, 21348866, 22241717, 22517554). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6903). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 01, 2001)
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no assertion criteria provided
Method: literature only
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PARAGANGLIOMAS 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027509.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 10, 2020 |
Comment on evidence:
Gimenez-Roqueplo et al. (2001) studied a French family in which a father and his elder son had bilateral neck paragangliomas, whereas the second son had … (more)
Gimenez-Roqueplo et al. (2001) studied a French family in which a father and his elder son had bilateral neck paragangliomas, whereas the second son had a left carotid body paraganglioma and an ectopic mediastinal pheochromocytoma (168000). A nonsense mutation (R22X) in the SDHD gene was found in these 3 subjects. Loss of heterozygosity was observed for the maternal chromosome 11q21-q25 within the tumor, but not in peripheral leukocytes. Assessment of the activity of respiratory-chain enzymes showed a complete and selective loss of complex II enzymatic activity in the inherited pheochromocytoma, which was not detected in 6 sporadic pheochromocytomas. In situ hybridization and immunohistochemistry experiments showed a high level of expression of markers of the angiogenic pathway. RT-PCR measurements confirmed that vascular endothelial growth factor (VEGF; 192240) and endothelial PAS domain protein-1 (EPAS1; 603349) mRNA levels were significantly higher than those observed in sporadic benign pheochromocytomas. Thus, inactivation of the SDHD gene in hereditary paraganglioma was associated with a complete loss of mitochondrial complex II activity and with a high expression of angiogenic factors. The overexpression of angiogenic factors may stimulate angiogenesis and therefore promote tumor growth. It has been suggested that mitochondria are the primary site of oxygen sensing in the carotid body (Prabhakar, 2000). Gimenez-Roqueplo et al. (2001) noted that several angiogenic markers that may be involved in tissue adaptation to hypoxia had been observed in inherited paragangliomas. (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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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 |
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 |
Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. | Piccini V | Endocrine-related cancer | 2012 | PMID: 22241717 |
High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. | Hensen EF | Clinical genetics | 2012 | PMID: 21348866 |
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 |
Genetics of pheochromocytoma and paraganglioma in Spanish patients. | Cascón A | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19258401 |
Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. | Benn DE | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16317055 |
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 |
The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. | Gimenez-Roqueplo AP | American journal of human genetics | 2001 | PMID: 11605159 |
Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene. | Taschner PE | Genes, chromosomes & cancer | 2001 | PMID: 11391798 |
Oxygen sensing by the carotid body chemoreceptors. | Prabhakar NR | Journal of applied physiology (Bethesda, Md. : 1985) | 2000 | PMID: 10846047 |
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Text-mined citations for rs104894306 ...
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.