ClinVar Genomic variation as it relates to human health
NM_003002.4(SDHD):c.57del (p.Leu20fs)
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.57del (p.Leu20fs)
Variation ID: 6917 Accession: VCV000006917.15
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11q23.1 11: 112087861 (GRCh38) [ NCBI UCSC ] 11: 111958585 (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 11, 2015 Feb 28, 2024 Jan 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003002.4:c.57del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002993.1:p.Leu20fs frameshift NM_001276503.2:c.57del NP_001263432.1:p.Leu20fs frameshift NM_001276504.2:c.52+902del intron variant NM_001276506.2:c.57del NP_001263435.1:p.Leu20fs frameshift NM_003002.2:c.57delG NR_077060.2:n.92del non-coding transcript variant NC_000011.10:g.112087861del NC_000011.9:g.111958585del NG_012337.3:g.6015del NG_033145.1:g.3938del LRG_9:g.6015del LRG_9t1:c.57del LRG_9p1:p.Leu20fs - Protein change
- L20fs
- Other names
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- Canonical SPDI
- NC_000011.10:112087860: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.
Exome Aggregation Consortium (ExAC) 0.00001
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
Help
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 | 764 |
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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Jan 1, 2008 | RCV000007326.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 10, 2024 | RCV002512872.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 26, 2022 | RCV000482313.11 | |
Pathogenic (1) |
criteria provided, single submitter
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May 20, 2022 | RCV000492772.9 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 17, 2020 | RCV000505302.9 |
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 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary Paraganglioma-Pheochromocytoma Syndromes
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001337824.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: SDHD c.57delG (p.Leu20CysfsX66) 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.57delG (p.Leu20CysfsX66) 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 251434 control chromosomes. c.57delG has been reported in the literature in individuals from at-least one family affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome/Carney-Stratakis dyad (McWhinney_2007, Pasini_2008, Ghayee_2009, Lodish_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 citing overlapping evidence utilized in the context of this evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 20, 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: SCV000581225.5
First in ClinVar: Jul 01, 2017 Last updated: Nov 29, 2022 |
Comment:
The c.57delG pathogenic mutation, located in coding exon 2 of the SDHD gene, results from a deletion of one nucleotide at nucleotide position 57, causing … (more)
The c.57delG pathogenic mutation, located in coding exon 2 of the SDHD gene, results from a deletion of one nucleotide at nucleotide position 57, causing a translational frameshift with a predicted alternate stop codon (p.L20Cfs*66). This alteration has been previously identified in individuals with paraganglioma(s) and gastrointestinal stromal tumor (GIST) (Pasini B et al. Eur. J. Hum. Genet. 2008 Jan;16(1):79-88; Lodish MB et al. Endocr. Relat. Cancer 2010 Sep;17(3):581-8; Wang YM et al. World J. Gastroenterol. 2015 Feb;21(8):2303-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
(Jan 10, 2024)
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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: SCV000762660.3
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu20Cysfs*66) 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.Leu20Cysfs*66) 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 gastrointestinal stromal tumor, pheochromocytoma, and multiple paragangliomas (PMID: 17667967). ClinVar contains an entry for this variant (Variation ID: 6917). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 26, 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: SCV000565548.7
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Pasini 2008, Andrews 2018, Caetano 2021); Frameshift variant predicted … (more)
Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Pasini 2008, Andrews 2018, Caetano 2021); Frameshift 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: 17804857, 19075037, 17973943, 26916530, 23036227, 25741136, 27051561, 20418362, 29386252, Caetano2021[Case Report], 17667967, 30787465) (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: yes
Allele origin:
germline
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Section on Medical Neuroendocrinolgy, National Institutes of Health
Accession: SCV000599532.1
First in ClinVar: Sep 15, 2017 Last updated: Sep 15, 2017 |
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Pathogenic
(Jan 01, 2008)
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no assertion criteria provided
Method: literature only
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PARAGANGLIOMA AND GASTRIC STROMAL SARCOMA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027524.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 10, 2020 |
Comment on evidence:
In a male patient with paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified a 1-bp deletion (57delG) in the SDHD gene. Pasini … (more)
In a male patient with paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified a 1-bp deletion (57delG) in the SDHD gene. Pasini et al. (2008) provided further information on this patient. He presented at 19 years of age with melena from a gastrointestinal tumor; at age 21 he had a right carotid body tumor and left adrenal pheochromocytoma, and 1 year later a left glomus jugular tumor was excised. At age 32, he presented with metastatic paraganglioma. The mutation was predicted to cause a frameshift and a premature stop codon at position 85. (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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Succinate dehydrogenase-deficient gastrointestinal stromal tumors. | Wang YM | World journal of gastroenterology | 2015 | PMID: 25741136 |
Succinate dehydrogenase gene mutations are strongly associated with paraganglioma of the organ of Zuckerkandl. | Lodish MB | Endocrine-related cancer | 2010 | PMID: 20418362 |
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 |
Mediastinal paragangliomas: association with mutations in the succinate dehydrogenase genes and aggressive behavior. | Ghayee HK | Endocrine-related cancer | 2009 | PMID: 19075037 |
Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. | Pasini B | European journal of human genetics : EJHG | 2008 | PMID: 17667967 |
Familial gastrointestinal stromal tumors and germ-line mutations. | McWhinney SR | The New England journal of medicine | 2007 | PMID: 17804857 |
Text-mined citations for rs587776649 ...
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.