NM_003002.4(SDHD):c.341A>G (p.Tyr114Cys) AND none provided

Clinical significance:Pathogenic (Last evaluated: Jul 26, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001289818.2

Allele description [Variation Report for NM_003002.4(SDHD):c.341A>G (p.Tyr114Cys)]

NM_003002.4(SDHD):c.341A>G (p.Tyr114Cys)

Gene:
SDHD:succinate dehydrogenase complex subunit D [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q23.1
Genomic location:
Preferred name:
NM_003002.4(SDHD):c.341A>G (p.Tyr114Cys)
HGVS:
  • NC_000011.10:g.112094831A>G
  • NG_012337.3:g.12985A>G
  • NM_001276503.2:c.196A>G
  • NM_001276504.2:c.224A>G
  • NM_001276506.2:c.*39A>G
  • NM_003002.4:c.341A>GMANE SELECT
  • NP_001263432.1:p.Met66Val
  • NP_001263433.1:p.Tyr75Cys
  • NP_002993.1:p.Tyr114Cys
  • LRG_9t1:c.341A>G
  • LRG_9:g.12985A>G
  • LRG_9p1:p.Tyr114Cys
  • NC_000011.9:g.111965555A>G
  • NM_003002.2:c.341A>G
  • NM_003002.3:c.341A>G
  • NR_077060.2:n.430A>G
  • O14521:p.Tyr114Cys
Protein change:
M66V; TYR114CYS
Links:
UniProtKB: O14521#VAR_017872; OMIM: 602690.0007; dbSNP: rs104894304
NCBI 1000 Genomes Browser:
rs104894304
Molecular consequence:
  • NM_001276506.2:c.*39A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001276503.2:c.196A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276504.2:c.224A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003002.4:c.341A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_077060.2:n.430A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
none provided
Identifiers:
MedGen: CN235283

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001477811ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Jul 26, 2019)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001477811.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 2, 2021

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