ClinVar Genomic variation as it relates to human health
NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp)
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.
Pathogenic(2); Likely pathogenic(5); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp)
Variation ID: 160358 Accession: VCV000160358.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5p15.33 5: 251427 (GRCh38) [ NCBI UCSC ] 5: 251542 (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 Nov 26, 2014 Apr 15, 2024 Jan 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004168.4:c.1753C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004159.2:p.Arg585Trp missense NM_001294332.2:c.1609C>T NP_001281261.1:p.Arg537Trp missense NM_001330758.2:c.1552-2966C>T intron variant NC_000005.10:g.251427C>T NC_000005.9:g.251542C>T NG_012339.1:g.38187C>T LRG_315:g.38187C>T LRG_315t1:c.1753C>T LRG_315p1:p.Arg585Trp - Protein change
- R585W, R537W
- Other names
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- Canonical SPDI
- NC_000005.10:251426: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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 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
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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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SDHA | - | - |
GRCh38 GRCh37 |
- | 2775 |
Conditions - Germline
Condition
Help
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Apr 24, 2023 | RCV000148027.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 14, 2021 | RCV000163558.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 15, 2024 | RCV000464783.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765834.4 | |
Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 26, 2022 | RCV000762143.22 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 5, 2022 | RCV001824123.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 15, 2023 | RCV003474794.1 |
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
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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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Uncertain significance
(Nov 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 5
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000785685.2
First in ClinVar: Sep 10, 2016 Last updated: Sep 10, 2016 |
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex II deficiency, nuclear type 1
Leigh syndrome Dilated cardiomyopathy 1GG Paragangliomas 5
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000897229.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Feb 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with ataxia and late-onset optic atrophy
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002073763.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
The c.1753C>T;p.(Arg585Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 160358; PMID: 21752896; 23666964; 28500238; … (more)
The c.1753C>T;p.(Arg585Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 160358; PMID: 21752896; 23666964; 28500238; 25720320; 29177515; 30050099) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Succ_DH_flav_C) - PM1. The variant is present at low allele frequencies population databases (rs200397144 – gnomAD 0.00001314%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Pathogenic
(Apr 14, 2021)
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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: SCV000214116.6
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The p.R585W pathogenic mutation (also known as c.1753C>T), located in coding exon 13 of the SDHA gene, results from a C to T substitution at … (more)
The p.R585W pathogenic mutation (also known as c.1753C>T), located in coding exon 13 of the SDHA gene, results from a C to T substitution at nucleotide position 1753. The arginine at codon 585 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been identified in multiple individuals with paraganglioma, pheochromocytoma or gastrointestinal stromal tumor (Korpershoek E et al. J. Clin. Endocrinol. Metab. 2011 Sep;96:E1472-6; Rattenberry E et al. J. Clin. Endocrinol. Metab. 2013 Jul;98:E1248-56; Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; Boikos SA et al. JAMA Oncol, 2016 Jul;2:922-8; Casey RT et al. Mol. Genet. Genomic Med. 2017 May;5:237-250; Tufton N et al. Endocr. Relat. Cancer 2017 Jul;24:L43-L49; van der Tuin K et al. J. Clin. Endocrinol. Metab. 2018 Feb;103:438-445; Richter S et al. Genet Med, 2019 03;21:705-717). Another alteration at the same codon, p.R585Q (c.1754G>A), has been detected in multiple individuals with paraganglioma or pheochromocytoma (Currás-Freixes M et al. J Med Genet, 2015 Oct;52:647-56; Ben Aim L et al. J Med Genet, 2019 08;56:513-520; Ambry internal data). Based on internal structural analysis, p.R585W is anticipated to result in a decrease in structural stability (Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(May 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: SCV002521995.2
First in ClinVar: Jun 05, 2022 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22517557, 28196207, 22904323, 27011036, 29177515, 23666964, 28546994, 28500238, 25720320, 25394176, 21752896, 32621582, 29978154, 30050099) (less)
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Likely pathogenic
(Sep 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1GG
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004200570.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 5
Mitochondrial complex II deficiency, nuclear type 1
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: SCV000553888.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 585 of the SDHA protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 585 of the SDHA protein (p.Arg585Trp). This variant is present in population databases (rs200397144, gnomAD 0.005%). This missense change has been observed in individuals with paragangliomas and pheochromocytomas (PMID: 21752896, 23666964, 25720320, 28500238, 29177515, 30050099; Invitae). ClinVar contains an entry for this variant (Variation ID: 160358). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg585 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been observed in individuals with SDHA-related conditions (PMID: 30877234), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000892405.22
First in ClinVar: Mar 31, 2019 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 4
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Likely pathogenic
(Apr 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 5
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004045372.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 28546994, 21752896, 23666964]. … (more)
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 28546994, 21752896, 23666964]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Likely pathogenic
(-)
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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: SCV001807314.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(-)
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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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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956154.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Oct 17, 2023)
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no assertion criteria provided
Method: literature only
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PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000246127.3
First in ClinVar: Nov 26, 2014 Last updated: Oct 21, 2023 |
Comment on evidence:
In a French patient with paragangliomas (PGL5; 614165), Korpershoek et al. (2011) identified a heterozygous germline c.1753C-T transition (c.1753C-T, NM_004168) in the SDHA gene, resulting … (more)
In a French patient with paragangliomas (PGL5; 614165), Korpershoek et al. (2011) identified a heterozygous germline c.1753C-T transition (c.1753C-T, NM_004168) in the SDHA gene, resulting in an arg585-to-trp (R585W) substitution. The mutation was found in 1 (0.1%) of 972 Dutch controls. Tumor tissue showed loss of heterozygosity for SDHA and lack of SDHA and SDHB (185470) immunostaining. (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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Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. | Ben Aim L | Journal of medical genetics | 2019 | PMID: 30877234 |
Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. | Richter S | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30050099 |
Clinical Aspects of SDHA-Related Pheochromocytoma and Paraganglioma: A Nationwide Study. | van der Tuin K | The Journal of clinical endocrinology and metabolism | 2018 | PMID: 29177515 |
SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity. | Casey RT | Molecular genetics & genomic medicine | 2017 | PMID: 28546994 |
SDHA mutated paragangliomas may be at high risk of metastasis. | Tufton N | Endocrine-related cancer | 2017 | PMID: 28500238 |
Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. | Boikos SA | JAMA oncology | 2016 | PMID: 27011036 |
Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria. | Inaoka DK | International journal of molecular sciences | 2015 | PMID: 26198225 |
SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T). | Papathomas TG | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2015 | PMID: 25720320 |
A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. | Rattenberry E | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23666964 |
SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. | Korpershoek E | The Journal of clinical endocrinology and metabolism | 2011 | PMID: 21752896 |
Text-mined citations for rs200397144 ...
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.