ClinVar Genomic variation as it relates to human health
NM_003002.4(SDHD):c.129G>A (p.Trp43Ter)
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.129G>A (p.Trp43Ter)
Variation ID: 6913 Accession: VCV000006913.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.1 11: 112087933 (GRCh38) [ NCBI UCSC ] 11: 111958657 (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 May 29, 2016 May 1, 2024 Mar 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003002.4:c.129G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002993.1:p.Trp43Ter nonsense NM_001276503.2:c.129G>A NP_001263432.1:p.Trp43Ter nonsense NM_001276504.2:c.53-934G>A intron variant NM_001276506.2:c.129G>A NP_001263435.1:p.Trp43Ter nonsense NR_077060.2:n.164G>A non-coding transcript variant NC_000011.10:g.112087933G>A NC_000011.9:g.111958657G>A NG_012337.3:g.6087G>A NG_033145.1:g.3866C>T LRG_9:g.6087G>A LRG_9t1:c.129G>A LRG_9p1:p.Trp43Ter - Protein change
- W43*
- Other names
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- Canonical SPDI
- NC_000011.10:112087932: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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SDHD | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
648 | 786 |
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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Mar 29, 2023 | RCV000007322.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 6, 2018 | RCV000222413.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2017 | RCV000756632.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 6, 2021 | RCV002512871.9 |
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
(Aug 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884504.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The SDHD c.129G>A, p.Trp43Ter variant (rs104894308) has been reported in multiple families with head and neck paraganglioma (Benn 2008, Cascon 2002, Timmers 2008), and segregating … (more)
The SDHD c.129G>A, p.Trp43Ter variant (rs104894308) has been reported in multiple families with head and neck paraganglioma (Benn 2008, Cascon 2002, Timmers 2008), and segregating with affected individuals (Pigny 2008, Valesco 2005). It is listed as pathogenic in ClinVar (Variation ID: 6913), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Benn D et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006; 91(3):827-36. Cascon A et al. Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma. Eur J Hum Genet. 2002; 10(8):457-61. Pigny P et al. Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. J Clin Endocrinol Metab. 2008; 93(5):1609-15. Timmers H et al. Mutations associated with succinate dehydrogenase D-related malignant paragangliomas. Clin Endocrinol (Oxf). 2008; 68(4):561-6. Velasco A et al. Mutation analysis of the SDHD gene in four kindreds with familial paraganglioma: description of one novel germline mutation. Diagn Mol Pathol. 2005; 14(2):109-14. (less)
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Pathogenic
(Mar 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004019079.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Jul 06, 2021)
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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: SCV000645368.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp43*) 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.Trp43*) in the SDHD gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). This variant has been reported to segregate with paraganglioma in a single family (PMID: 18211978) and also has been observed in unrelated individuals with paraganglioma (PMID: 12111639, 19454582, 18561749, 20098451) and gastrointestinal stromal tumor (PMID: 20098451). This variant has been described as a likely common cause of disease in the Spanish population (PMID: 19258401). ClinVar contains an entry for this variant (Variation ID: 6913). (less)
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Pathogenic
(Nov 06, 2018)
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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: SCV000276168.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.W43* pathogenic mutation (also known as c.129G>A) located in coding exon 2 of the SDHD gene, results from a G to A substitution at … (more)
The p.W43* pathogenic mutation (also known as c.129G>A) located in coding exon 2 of the SDHD gene, results from a G to A substitution at nucleotide position 129. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. This pathogenic mutation has been identified in a patient with multiple paragangliomas (PGLs) and a family history of pheochromocytoma, and it has been predicted to lead to a protein that lacks the transmembrane, signal, and heme-binding domains (Cascon A et al. Eur. J. Hum. Genet. 2002 Aug; 10(8):457-61). The p.W43* pathogenic mutation has also been reported in a French female diagnosed with metastatic bilateral cartoid HNPGLs at age 22 who had no family history of PGLs (Timmers HJ et al. Clin. Endocrinol. (Oxf). 2008 Apr;68:561-6). 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)
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Pathogenic
(May 01, 2008)
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no assertion criteria provided
Method: literature only
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PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027520.5
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024 |
Comment on evidence:
In a patient with paragangliomas and a family history of pheochromocytoma (PPGL1; 168000), Cascon et al. (2002) identified a heterozygous c.129G-A transition in exon 2 … (more)
In a patient with paragangliomas and a family history of pheochromocytoma (PPGL1; 168000), Cascon et al. (2002) identified a heterozygous c.129G-A transition in exon 2 of the SDHD gene, resulting in a trp43-to-ter (W43X) substitution and a truncated protein of 43 amino acids. Pigny et al. (2008) reported a family with maternal transmission of the W43X mutation in the third generation. A boy received the mutation from his mother and developed a glomus tympanicum paraganglioma at 11 years of age. He shared only the 11q23 haplotype with the other affected members of the family. Methylation analysis of the differentially methylated region upstream of the maternally expressed H19 gene, mapped to 11p15, showed that the seventh CTCF binding site was hypermethylated in the germline of the affected boy, suggesting a gain of imprinting. The authors concluded that maternal transmission of a SDHD-linked paraganglioma, even if a rare event, can occur. The authors proposed that children who inherit a pathogenic mutation from their mother should be considered at risk for paraganglioma. (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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Paraganglioma syndrome type 1 in a patient with Carney-Stratakis syndrome. | Ayala-Ramirez M | Nature reviews. Endocrinology | 2010 | PMID: 20098451 |
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 |
W43X SDHD mutation in sporadic head and neck paraganglioma. | Galera-Ruiz H | Analytical and quantitative cytology and histology | 2008 | PMID: 18561749 |
Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. | Pigny P | The Journal of clinical endocrinology and metabolism | 2008 | PMID: 18211978 |
Mutations associated with succinate dehydrogenase D-related malignant paragangliomas. | Timmers HJ | Clinical endocrinology | 2008 | PMID: 17973943 |
Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma. | Cascon A | European journal of human genetics : EJHG | 2002 | PMID: 12111639 |
Text-mined citations for rs104894308 ...
HelpRecord last updated May 12, 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.