ClinVar Genomic variation as it relates to human health
NM_004168.4(SDHA):c.1534C>T (p.Arg512Ter)
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_004168.4(SDHA):c.1534C>T (p.Arg512Ter)
Variation ID: 371805 Accession: VCV000371805.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5p15.33 5: 240459 (GRCh38) [ NCBI UCSC ] 5: 240574 (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 Jan 7, 2017 Apr 20, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004168.4:c.1534C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004159.2:p.Arg512Ter nonsense NM_001294332.2:c.1390C>T NP_001281261.1:p.Arg464Ter nonsense NM_001330758.2:c.1534C>T NP_001317687.1:p.Arg512Ter nonsense NC_000005.10:g.240459C>T NC_000005.9:g.240574C>T NG_012339.1:g.27219C>T LRG_315:g.27219C>T LRG_315t1:c.1534C>T LRG_315p1:p.Arg512Ter - Protein change
- R512*, R464*
- Other names
- p.Arg512*
- Canonical SPDI
- NC_000005.10:240458: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.
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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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SDHA | - | - |
GRCh38 GRCh37 |
2620 | 2776 |
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
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
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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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 21, 2023 | RCV000411416.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2021 | RCV000566844.4 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 3, 2022 | RCV000578965.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV000684799.9 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV002285327.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2021 | RCV002502437.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 21, 2023 | RCV003475994.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 30, 2022 | RCV004017601.1 |
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
Help
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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Pathogenic
(Mar 11, 2021)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001786670.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
The SDHA c.1534C>T (p.Arg512Ter) variant is a stop-gained variant that is predicted to result in a premature termination or absence of the protein. The p.Arg512Ter … (more)
The SDHA c.1534C>T (p.Arg512Ter) variant is a stop-gained variant that is predicted to result in a premature termination or absence of the protein. The p.Arg512Ter variant has been reported in two studies in which it was identified as a germline variant in at least two affected individuals including one individual with a paraganglioma and one individual with a gastrointestinal stromal tumor (Wagner et al. 2013; Papathomas et al. 2015). The p.Arg512Ter variant is reported at a frequency of 0.000078 in the European (non-Finnish) population from of the Genome Aggregation Database. This allele frequency is high but is may be consistent with reduced penetrance. Based on the available evidence and application of the ACMG criteria, the p.Arg512Ter variant is classified as pathogenic for hereditary pheochromocytoma-paraganglioma syndrome. (less)
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Pathogenic
(Jan 01, 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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502821.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
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Pathogenic
(Nov 01, 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: SCV002527721.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
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Pathogenic
(Oct 29, 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: SCV000664526.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R512* pathogenic mutation (also known as c.1534C>T), located in coding exon 11 of the SDHA gene, results from a C to T substitution at … (more)
The p.R512* pathogenic mutation (also known as c.1534C>T), located in coding exon 11 of the SDHA gene, results from a C to T substitution at nucleotide position 1534. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation has been reported in both the germline and in the tumor of an individual with an extra-adrenal paraganglioma and in the germline of an individual with a testis paraganglioma (Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; van der Tuin K et al. J. Clin. Endocrinol. Metab. 2018 02;103(2):438-445). In another study, the mutation was carried by a 53-year-old female with metastatic retroperitoneal paraganglioma (Jha A et al. Front Oncol, 2019 Feb;9:53). This mutation has also been identified in several individuals with SDHA-deficient gastrointestinal stromal tumors (Wagner AJ et al. Mod Pathol, 2013 Feb;26:289-94; Jha A et al. Front Oncol, 2019 Feb;9:53). 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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Likely pathogenic
(Dec 13, 2015)
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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: SCV000488005.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Sep 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex II deficiency, nuclear type 1
Dilated cardiomyopathy 1GG Paragangliomas 5 Neurodegeneration with ataxia and late-onset optic atrophy
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811147.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 03, 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: SCV000680783.4
First in ClinVar: Feb 13, 2018 Last updated: Mar 04, 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); Identified in patients with personal and family history consistent with pathogenic variants in this gene (Wagner 2013, Papathomas 2015, Maniam 2018, van der Tuin 2018, Ben Aim 2019); This variant is associated with the following publications: (PMID: 22955521, 25720320, 27011036, 28768491, 28546994, 24886695, 28748451, 23730622, 29978154, 31589614, 30877234, 31981491, 29177515, 32581362) (less)
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Pathogenic
(Apr 21, 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: SCV004018616.1
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
(Aug 21, 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: SCV004200590.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Jan 25, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225946.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP4, PVS1
Number of individuals with the variant: 1
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Pathogenic
(Jan 28, 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: SCV000553882.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg512*) in the SDHA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg512*) in the SDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is present in population databases (rs748089700, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with paraganglioma and/or gastrointestinal stromal tumor (PMID: 22955521, 25720320). ClinVar contains an entry for this variant (Variation ID: 371805). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002497299.12
First in ClinVar: Apr 08, 2022 Last updated: Apr 15, 2024 |
Comment:
SDHA: PVS1
Number of individuals with the variant: 1
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Pathogenic
(Jun 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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848632.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg512X variant in SDHA has been reported in 5 individuals with SDHA-related tumors (paragangliomas, pheochromocytomas, GISTs) and segregated with disease in 2 affected individuals … (more)
The p.Arg512X variant in SDHA has been reported in 5 individuals with SDHA-related tumors (paragangliomas, pheochromocytomas, GISTs) and segregated with disease in 2 affected individuals from 2 families (Wagner 2013 PMID: 22955521, Papathomas 2015 PMID: 25720320, van der tuin 2018 PMID: 29177515, Ben Aim 2019 PMID: 30877234, Whitworth 2021 PMID: 33854214). It has also been identified in 0.009% (6/68038) of European chromosomes by gnomAD v. 3 (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 371805). This nonsense variant leads to a premature termination codon at position 512, which is predicted to lead to a truncated or absent protein. Loss of function of the SDHA gene is an established disease mechanism in autosomal dominant Hereditary paraganglioma-pheochromocytoma syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Hereditary paraganglioma-pheochromocytoma. ACMG/AMP Criteria applied: PS4, PVS1, PM2_P. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Opsoclonus-myoclonus syndrome
(Sporadic)
Affected status: yes
Allele origin:
de novo
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Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe
Accession: SCV002573785.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Clinical Features:
Opsoclonus (present) , Myoclonus (present)
Age: 10-19 years
Sex: female
Geographic origin: Brazil
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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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Familial wild-type gastrointestinal stromal tumour in association with germline truncating variants in both SDHA and PALB2. | Whitworth J | European journal of human genetics : EJHG | 2021 | PMID: 33854214 |
Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. | Satterstrom FK | Cell | 2020 | PMID: 31981491 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. | Ben Aim L | Journal of medical genetics | 2019 | PMID: 30877234 |
Clinical, Diagnostic, and Treatment Characteristics of SDHA-Related Metastatic Pheochromocytoma and Paraganglioma. | Jha A | Frontiers in oncology | 2019 | PMID: 30854332 |
Pathogenicity and Penetrance of Germline SDHA Variants in Pheochromocytoma and Paraganglioma (PPGL). | Maniam P | Journal of the Endocrine Society | 2018 | PMID: 29978154 |
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 |
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 |
SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors. | Renkema GH | European journal of human genetics : EJHG | 2015 | PMID: 24781757 |
Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors. | Wagner AJ | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2013 | PMID: 22955521 |
SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors. | Italiano A | BMC cancer | 2012 | PMID: 22974104 |
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Text-mined citations for rs748089700 ...
HelpRecord last updated Apr 20, 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.