ClinVar Genomic variation as it relates to human health
NM_003002.4(SDHD):c.341A>G (p.Tyr114Cys)
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.341A>G (p.Tyr114Cys)
Variation ID: 6900 Accession: VCV000006900.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.1 11: 112094831 (GRCh38) [ NCBI UCSC ] 11: 111965555 (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 Sep 14, 2017 Feb 28, 2024 Apr 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003002.4:c.341A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002993.1:p.Tyr114Cys missense NM_001276503.2:c.196A>G NP_001263432.1:p.Met66Val missense NM_001276504.2:c.224A>G NP_001263433.1:p.Tyr75Cys missense NM_001276506.2:c.*39A>G 3 prime UTR NR_077060.2:n.430A>G non-coding transcript variant NC_000011.10:g.112094831A>G NC_000011.9:g.111965555A>G NG_012337.3:g.12985A>G LRG_9:g.12985A>G LRG_9t1:c.341A>G LRG_9p1:p.Tyr114Cys O14521:p.Tyr114Cys - Protein change
- Y114C, M66V, Y75C
- Other names
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- Canonical SPDI
- NC_000011.10:112094830:A: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.
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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 |
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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May 15, 2001 | RCV000007309.14 | |
Pathogenic (2) |
criteria provided, single submitter
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May 20, 2013 | RCV000155750.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 22, 2021 | RCV000221353.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 13, 2023 | RCV002228004.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 2, 2022 | RCV001810833.14 |
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
(May 20, 2013)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000205461.5
First in ClinVar: Jan 31, 2015 Last updated: Sep 14, 2017 |
Comment:
The Tyr114Cys variant in SDHD was originally reported in one German individual w ith familial paraganglioma (Milunsky, 2001) and subsequently reported in one Aus trian … (more)
The Tyr114Cys variant in SDHD was originally reported in one German individual w ith familial paraganglioma (Milunsky, 2001) and subsequently reported in one Aus trian individual with hereditary neck paraganglioma (HNPGL) where the variant se gregated with disease in 7 affected relatives from the same family (Fish, 2007). Recently, the Tyr114Cys variant has been reported to have arisen as a founder effect in a population originating from the region surrounding Torentino, Italy (Schiavi, 2012). Schiavi and colleagues studied 15 Italian index cases with HNPG L and found the Tyr114Cys variant segregated with disease in 138 affected relati ves from 95 families (Schiavi, 2012). Functional studies have shown that the Tyr 114Cys variant impacts protein function, and results in complete loss of ubiquin one reductase activity in yeast (Panizza, 2013). However, this in vitro assay ma y not accurately represent biological function. This variant has not been identi fied in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Tyr1 14Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria t o be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segrega tion studies, absence from controls and functional evidence supporting the varia nt causing a functional defect on the protein. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 26, 2019)
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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: SCV001477811.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The SDHD c.341A>G; p.Tyr114Cys variant (rs104894304) is reported in the literature in multiple individuals and families affected with pheochromocytoma or paraganglioma (Andrews 2018, Antonello 2008, … (more)
The SDHD c.341A>G; p.Tyr114Cys variant (rs104894304) is reported in the literature in multiple individuals and families affected with pheochromocytoma or paraganglioma (Andrews 2018, Antonello 2008, Benn 2006, Braun 2005, Fish 2007, Milunsky 2001, Neumann 2004, Piccini 2012, Richter 2019), and is a common variant in Italy due to a founder effect (Schiavi 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 6900), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 114 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses in yeast demonstrate a complete loss of ubiquinone reductase activity (Panizza 2013). Based on available information, this variant is considered to be pathogenic. References: Andrews KA et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018 Jun;55(6):384-394. Antonello M et al. Role of the genetic study in the management of carotid body tumor in paraganglioma syndrome. Eur J Vasc Endovasc Surg. 2008 Nov;36(5):517-9. Benn DE et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36. Braun S et al. Active succinate dehydrogenase (SDH) and lack of SDHD mutations in sporadic paragangliomas. Anticancer Res. 2005 Jul-Aug;25(4):2809-14. Fish JH et al. Systematic screening and treatment evaluation of hereditary neck paragangliomas. Head Neck. 2007 Sep;29(9):864-73. Milunsky JM et al. Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma. Am J Med Genet. 2001 May 15;100(4):311-4. Neumann HP et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. Panizza E et al. Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. Hum Mol Genet. 2013 Feb 15;22(4):804-15. Piccini V et al. Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. Endocr Relat Cancer. 2012 Apr 10;19(2):149-55. Richter S et al. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet Med. 2019 Mar;21(3):705-717. Schiavi F et al. The endemic paraganglioma syndrome type 1: origin, spread, and clinical expression. J Clin Endocrinol Metab. 2012 Apr;97(4):E637-41. (less)
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Pathogenic
(Sep 28, 2017)
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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: SCV000275206.7
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.Y114C pathogenic mutation (also known as c.341A>G), located in exon 4 of the SDHD gene, results from an A to G substitution at nucleotide … (more)
The p.Y114C pathogenic mutation (also known as c.341A>G), located in exon 4 of the SDHD gene, results from an A to G substitution at nucleotide position 341. The tyrosine at codon 114 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been identified in multiple individuals affected with paragangliomas (PGL) and/or pheochromocytomas (Neumann H et al. JAMA. 2004 Aug 25;292(8):943-51; Liapis C et al. Anticancer Res. 2005 May-Jun;25(3c):2449-52; Benn D et al. J. Clin. Endocrinol. Metab. 2006 Mar;91(3):827-36; Antonello M et al. Eur. J. Vasc. Endovasc. Surg. 2008 Nov;36(5):517-9; Piccini V et al. Endocr. Relat. Cancer. 2012 Apr 10;19(2):149-55; Zdrojowy-Wena A and Bednarek-Tupikowska G. Neuro Endocrinol. Lett. 2014;35(5):355-8; Bennedbæk M et al. Hered. Cancer Clin. Pract. 2016 Jun;14:13). In addition, this mutation showed strong segregation with disease among 38 screened members of a family affected with head and neck PGL (Fish J et al. Head Neck. 2007 Sep;29(9):864-73). Another study indicated that the p.Y114C mutation in the SDHD gene is an Italian founder mutation after finding this alteration in 287 out of 540 individuals from 95 kindred who were diagnosed with head and neck PGL (Schiavi et al. J. Clin. Endocrinol. Metab. 2012 Apr;97(4):637-41). 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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Pathogenic
(Apr 13, 2023)
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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: SCV000823357.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
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) … (more)
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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. ClinVar contains an entry for this variant (Variation ID: 6900). This missense change has been observed in individuals with pheochromocytomas and paragangliomas (PMID: 11343322, 16080474, 16317055, 17563904, 22456618, 23433498, 25275255, 27279923, 29386252). It is commonly reported in individuals of Trentino Italian ancestry (PMID: 22456618). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 114 of the SDHD protein (p.Tyr114Cys). Experimental studies have shown that this missense change affects SDHD function (PMID: 23175444). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 22, 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: SCV002527126.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Pathogenic
(Nov 02, 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: SCV002599968.2
First in ClinVar: Nov 13, 2022 Last updated: Mar 04, 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; Published functional studies demonstrate a damaging effect: protein instability, reduced SDH enzyme activity, and increased mtDNA mutability and sensitivity to oxidative stress (Panizza et al., 2013; Chang et al., 2015); This variant is associated with the following publications: (PMID: 17208193, 26916530, 19454582, 30050099, 34906457, 23175444, 22456618, 16080530, 15066320, 21792967, 18826997, 26259135, 26549015, 15883710, 15988378, 25394176, 22241717, 18692411, 16317055, 21844248, 27279923, 16080474, 15328326, 11343322, 9295078, 29386252, 23433498, 17102086, 25275255, 30375904, 34939938, 17563904, 25328978) (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: SCV000599544.1
First in ClinVar: Sep 14, 2017 Last updated: Sep 14, 2017 |
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Pathogenic
(May 15, 2001)
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no assertion criteria provided
Method: literature only
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PARAGANGLIOMAS 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027506.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 10, 2020 |
Comment on evidence:
In affected members of a German family with hereditary paragangliomas (PGL1; 168000), Milunsky et al. (2001) identified a missense mutation in exon 4 of the … (more)
In affected members of a German family with hereditary paragangliomas (PGL1; 168000), Milunsky et al. (2001) identified a missense mutation in exon 4 of the SDHD gene, resulting in a tyr114-to-cys (Y114C) substitution. This nonconservative amino acid substitution could alter the conformation of the protein. (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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Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. | Andrews KA | Journal of medical genetics | 2018 | PMID: 29386252 |
Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients. | Bennedbæk M | Hereditary cancer in clinical practice | 2016 | PMID: 27279923 |
Challenges in the diagnosis of pheochromocytoma and paraganglioma syndrome. | Zdrojowy-Wełna A | Neuro endocrinology letters | 2014 | PMID: 25275255 |
Paraganglioma of the carotid body: treatment strategy and SDH-gene mutations. | Fruhmann J | European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery | 2013 | PMID: 23433498 |
Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. | Panizza E | Human molecular genetics | 2013 | PMID: 23175444 |
The endemic paraganglioma syndrome type 1: origin, spread, and clinical expression. | Schiavi F | The Journal of clinical endocrinology and metabolism | 2012 | PMID: 22456618 |
Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. | Piccini V | Endocrine-related cancer | 2012 | PMID: 22241717 |
Role of the genetic study in the management of carotid body tumor in paraganglioma syndrome. | Antonello M | European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery | 2008 | PMID: 18692411 |
Systematic screening and treatment evaluation of hereditary neck paragangliomas. | Fish JH | Head & neck | 2007 | PMID: 17563904 |
Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. | Benn DE | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16317055 |
Carotid body paraganglioma and SDHD mutation in a Greek family. | Liapis CD | Anticancer research | 2005 | PMID: 16080474 |
Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma. | Milunsky JM | American journal of medical genetics | 2001 | PMID: 11343322 |
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Text-mined citations for rs104894304 ...
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.