NM_003002.4(SDHD):c.341A>G (p.Tyr114Cys) AND Hereditary Paraganglioma-Pheochromocytoma Syndromes

Clinical significance:Pathogenic (Last evaluated: May 20, 2013)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000155750.2

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]
Observations:
1

Condition(s)

Name:
Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL-PCC)
Synonyms:
Hereditary Paragangliomas and Pheochromocytomas
Identifiers:
MONDO: MONDO:0017366; MedGen: C1708353

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000205461Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(May 20, 2013)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000599544Section on Medical Neuroendocrinolgy,National Institutes of Healthno assertion criteria providedPathogenicgermlineresearch

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma.

Milunsky JM, Maher TA, Michels VV, Milunsky A.

Am J Med Genet. 2001 May 15;100(4):311-4.

PubMed [citation]
PMID:
11343322

Systematic screening and treatment evaluation of hereditary neck paragangliomas.

Fish JH, Klein-Weigel P, Biebl M, Janecke A, Tauscher T, Fraedrich G.

Head Neck. 2007 Sep;29(9):864-73.

PubMed [citation]
PMID:
17563904
See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000205461.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Section on Medical Neuroendocrinolgy,National Institutes of Health, SCV000599544.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 2, 2021

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