ClinVar Genomic variation as it relates to human health
NM_003002.4(SDHD):c.53C>T (p.Ala18Val)
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.
Uncertain significance(9); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003002.4(SDHD):c.53C>T (p.Ala18Val)
Variation ID: 302481 Accession: VCV000302481.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.1 11: 112087857 (GRCh38) [ NCBI UCSC ] 11: 111958581 (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 Dec 6, 2016 Feb 28, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003002.4:c.53C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002993.1:p.Ala18Val missense NM_001276503.2:c.53C>T NP_001263432.1:p.Ala18Val missense NM_001276504.2:c.52+898C>T intron variant NM_001276506.2:c.53C>T NP_001263435.1:p.Ala18Val missense NR_077060.2:n.88C>T non-coding transcript variant NC_000011.10:g.112087857C>T NC_000011.9:g.111958581C>T NG_012337.3:g.6011C>T NG_033145.1:g.3942G>A LRG_9:g.6011C>T LRG_9t1:c.53C>T LRG_9p1:p.Ala18Val - Protein change
- A18V
- Other names
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- Canonical SPDI
- NC_000011.10:112087856: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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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00007
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00012
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 29, 2021 | RCV000344579.18 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Jul 26, 2023 | RCV000506525.20 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 9, 2022 | RCV000571997.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 11, 2023 | RCV002288968.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 17, 2024 | RCV002229954.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 24, 2023 | RCV003475929.1 |
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
Help
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
Help
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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Likely benign
(Apr 28, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000367343.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Feb 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000602188.3
First in ClinVar: Sep 30, 2017 Last updated: Jan 26, 2021 |
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Uncertain significance
(Nov 12, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002535345.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
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Uncertain significance
(Sep 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580240.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
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Uncertain significance
(Sep 29, 2021)
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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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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002012410.2
First in ClinVar: Nov 11, 2021 Last updated: Dec 24, 2022 |
Comment:
The SDHD c.53C>T (p.Ala18Val) missense change has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-111958581-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about … (more)
The SDHD c.53C>T (p.Ala18Val) missense change has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-111958581-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. In addition, algorithms that predict the impact of sequence changes on splicing indicate that this variant does not affect splicing. This variant has been reported in an individual with an ACTH-secreting pituitary adenoma, mild neurocognitive defects, and anxiety (PMID: 25695889, 30273935). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no evidence criteria applied. (less)
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Uncertain significance
(Dec 09, 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: SCV000675111.5
First in ClinVar: Jan 01, 2018 Last updated: Apr 15, 2023 |
Comment:
The p.A18V variant (also known as c.53C>T) is located in coding exon 2 of the SDHD gene. The alanine at codon 18 is replaced by … (more)
The p.A18V variant (also known as c.53C>T) is located in coding exon 2 of the SDHD gene. The alanine at codon 18 is replaced by valine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 2. This alteration was reported in one individual with a sporadic pituitary adenoma (Xekoui et al. J. Clin. Endocrinol. Metab. 2015 May;100(5): E710-9). It has also been reported in a patient diagnosed with a carotid body tumor at age 48 (Sen I et al. J Vasc Surg, 2020 May;71:1602-1612.e2). However, this variant has been detected in multiple individuals with no reported features of SDHD-associated disease (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jul 26, 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: SCV001789667.4
First in ClinVar: Aug 21, 2021 Last updated: Aug 13, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with head/neck paraganglioma or pituitary adenoma (Xekouki et al., 2015; Sen et al., 2020); This variant is associated with the following publications: (PMID: 25695889, 28873162, 32035780, 30273935, 36149413, 35938916) (less)
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Uncertain significance
(Oct 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 2 deficiency, nuclear type 3
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004203086.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(May 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 1
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004362299.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with valine at codon 18 of the SDHD protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces alanine with valine at codon 18 of the SDHD protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with head and neck paraganglioma and pituitary adenoma (PMID: 25695889, 32035780). This variant has been identified in 21/282830 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 17, 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: SCV000554055.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 18 of the SDHD protein (p.Ala18Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 18 of the SDHD protein (p.Ala18Val). This variant is present in population databases (rs192332761, gnomAD 0.01%). This missense change has been observed in individual(s) with a pituitary adenoma (PMID: 25695889). ClinVar contains an entry for this variant (Variation ID: 302481). 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 tolerated. 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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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809218.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742689.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965311.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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Tumor-specific prognosis of mutation-positive patients with head and neck paragangliomas. | Sen I | Journal of vascular surgery | 2020 | PMID: 32035780 |
The 3PAs: An Update on the Association of Pheochromocytomas, Paragangliomas, and Pituitary Tumors. | Xekouki P | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2019 | PMID: 30273935 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. | Xekouki P | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 25695889 |
Text-mined citations for rs192332761 ...
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.