ClinVar Genomic variation as it relates to human health
NM_003002.4(SDHD):c.112C>T (p.Arg38Ter)
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.112C>T (p.Arg38Ter)
Variation ID: 6893 Accession: VCV000006893.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.1 11: 112087916 (GRCh38) [ NCBI UCSC ] 11: 111958640 (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 Apr 4, 2013 Feb 28, 2024 Aug 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003002.4:c.112C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002993.1:p.Arg38Ter nonsense NM_001276503.2:c.112C>T NP_001263432.1:p.Arg38Ter nonsense NM_001276504.2:c.53-951C>T intron variant NM_001276506.2:c.112C>T NP_001263435.1:p.Arg38Ter nonsense NR_077060.2:n.147C>T non-coding transcript variant NC_000011.10:g.112087916C>T NC_000011.9:g.111958640C>T NG_012337.3:g.6070C>T NG_033145.1:g.3883G>A LRG_9:g.6070C>T LRG_9t1:c.112C>T LRG_9p1:p.Arg38Ter - Protein change
- R38*
- Other names
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- Canonical SPDI
- NC_000011.10:112087915: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 |
631 | 767 |
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) |
no assertion criteria provided
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May 9, 2002 | RCV000007296.15 | |
Pathogenic (1) |
no assertion criteria provided
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May 9, 2002 | RCV000007297.15 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 30, 2022 | RCV000020518.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 18, 2023 | RCV000486967.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 31, 2022 | RCV000492087.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 18, 2023 | RCV002228000.13 |
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
(Mar 30, 2022)
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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: SCV002500781.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: SDHD c.112C>T (p.Arg38X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: SDHD c.112C>T (p.Arg38X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251472 control chromosomes (gnomAD). c.112C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome and was shown to co-segregate with disease within families (e.g. Baysal_2000, Neumann_2002, Erlic_2009, Ding_2019). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 31, 2022)
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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: SCV000581231.5
First in ClinVar: Jul 01, 2017 Last updated: Nov 29, 2022 |
Comment:
The p.R38* pathogenic mutation (also known as c.112C>T), located in coding exon 2 of the SDHD gene, results from a C to T substitution at … (more)
The p.R38* pathogenic mutation (also known as c.112C>T), located in coding exon 2 of the SDHD gene, results from a C to T substitution at nucleotide position 112. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been reported in multiple individuals diagnosed with pheochromocytoma(s) and/or extra-adrenal paraganglioma(s) (Baysal BE et al. Science 2000 Feb;287(5454):848-51; Gimm O et al. Cancer Res. 2000 Dec;60(24):6822-5; Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Erlic Z et al. Clin. Cancer Res. 2009 Oct;15(20):6378-85; Lodish MB et al. Endocr. Relat. Cancer 2010 Sep;17(3):581-8). One study identified this mutation in an unaffected individual as well as in his two children who were both affected with paragangliomas (Fish JH et al. Head Neck 2007 Sep;29(9):864-73). 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
(Aug 18, 2023)
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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: SCV000568552.7
First in ClinVar: Apr 27, 2017 Last updated: Aug 24, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10657297, 12000816, 19825962, 12811540, 21348866, 12351569, 26273102, 12205103, 8981955, 27867439, 27700540, 33219105, 25525159, 11156372, 25791839, 17563904, 12364472, 22517557, 20418362, 11897817, 11391798, 15328326, 19454582, 26269449, 15066320, 22566157, 28748451, 27073498, 32561571, 34750850) (less)
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Pathogenic
(Mar 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731539.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Arg38X variant in SDHD has been reported in at least 9 individuals with SD HD-associated cancers, segregated with disease in at least 10 affected … (more)
The p.Arg38X variant in SDHD has been reported in at least 9 individuals with SD HD-associated cancers, segregated with disease in at least 10 affected relatives from multiple families (Gimm 2000, Baysal 2000;2002,Neumann 2004, Erlic 2009, B urnichon 2009, Hensen 2012, ClinVar ID#6893), and was absent from large populati on studies. This nonsense variant leads to a premature termination codon at posi tion 38, which is predicted to lead to a truncated or absent protein. Heterozygo us loss of function of the SDHD gene is an established disease mechanism in indi viduals with hereditary paragangliomas and pheochromocytomas. In summary, this v ariant meets criteria to be classified as pathogenic for hereditary paragangliom as and pheochromocytomas in an autosomal dominant manner based upon segregation studies and the predicted impact to the protein. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
(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: SCV002761360.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Aug 18, 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: SCV000287812.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6893). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6893). This premature translational stop signal has been observed in individual(s) with paraganglioma and pheochromocytoma (PMID: 10657297, 11156372, 11897817, 12000816, 15328326, 19454582, 19825962, 21348866, 26269449). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg38*) 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). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Hereditary pheochromocytoma-paraganglioma
Affected status: no
Allele origin:
germline
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Section on Medical Neuroendocrinolgy, National Institutes of Health
Accession: SCV000599535.1
First in ClinVar: Sep 14, 2017 Last updated: Sep 14, 2017 |
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Pathogenic
(May 09, 2002)
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no assertion criteria provided
Method: literature only
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PHEOCHROMOCYTOMA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027493.5
First in ClinVar: Apr 04, 2013 Last updated: Jan 10, 2020 |
Comment on evidence:
In a family with autosomal dominant hereditary paragangliomas (PGL1; 168000), Baysal et al. (2000) identified a C-to-T transition in the SDHD gene, resulting in an … (more)
In a family with autosomal dominant hereditary paragangliomas (PGL1; 168000), Baysal et al. (2000) identified a C-to-T transition in the SDHD gene, resulting in an arg38-to-ter (R38X) substitution within the mitochondrial signal peptide. Gimm et al. (2000) identified the R38X mutation in a 33-year-old woman with 2 extraadrenal pheochromocytomas, 1 intraabdominal and 1 intrathoracic. In the germlines of 2 unrelated patients with sporadic pheochromocytoma (171300), Neumann et al. (2002) identified the R38X substitution, resulting from a 112C-T transition in exon 2 of the SDHD gene. The mutation was not identified in 600 control chromosomes. (less)
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Pathogenic
(May 09, 2002)
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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: SCV000027492.5
First in ClinVar: Apr 04, 2013 Last updated: Jan 10, 2020 |
Comment on evidence:
In a family with autosomal dominant hereditary paragangliomas (PGL1; 168000), Baysal et al. (2000) identified a C-to-T transition in the SDHD gene, resulting in an … (more)
In a family with autosomal dominant hereditary paragangliomas (PGL1; 168000), Baysal et al. (2000) identified a C-to-T transition in the SDHD gene, resulting in an arg38-to-ter (R38X) substitution within the mitochondrial signal peptide. Gimm et al. (2000) identified the R38X mutation in a 33-year-old woman with 2 extraadrenal pheochromocytomas, 1 intraabdominal and 1 intrathoracic. In the germlines of 2 unrelated patients with sporadic pheochromocytoma (171300), Neumann et al. (2002) identified the R38X substitution, resulting from a 112C-T transition in exon 2 of the SDHD gene. The mutation was not identified in 600 control chromosomes. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Hereditary pheochromocytoma-paraganglioma
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000040975.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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Hereditary Paraganglioma-Pheochromocytoma Syndromes. | Adam MP | - | 2023 | PMID: 20301715 |
SDHx gene detection and clinical Phenotypic analysis of multiple paraganglioma in the head and neck. | Ding Y | The Laryngoscope | 2019 | PMID: 30484866 |
Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. | Currás-Freixes M | Journal of medical genetics | 2015 | PMID: 26269449 |
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 |
Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients. | Erlic Z | Clinical cancer research : an official journal of the American Association for Cancer Research | 2009 | PMID: 19825962 |
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 |
Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. | Neumann HP | JAMA | 2004 | PMID: 15328326 |
Germ-line mutations in nonsyndromic pheochromocytoma. | Neumann HP | The New England journal of medicine | 2002 | PMID: 12000816 |
Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. | Baysal BE | Journal of medical genetics | 2002 | PMID: 11897817 |
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 |
Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. | Gimm O | Cancer research | 2000 | PMID: 11156372 |
Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. | Baysal BE | Science (New York, N.Y.) | 2000 | PMID: 10657297 |
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Text-mined citations for rs80338843 ...
HelpRecord last updated Mar 23, 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.