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

Clinical significance:Pathogenic (Last evaluated: Oct 3, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000694891.4

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:
Carney-Stratakis syndrome
Synonyms:
Paraganglioma and gastric stromal sarcoma; Paraganglioma and gastrointestinal stromal tumor; Paraganglioma and GIST; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0011740; MedGen: C1847319; Orphanet: 97286; OMIM: 606864
Name:
Pheochromocytoma
Synonyms:
Chromaffinoma; Chromaffin paraganglioma; Chromaffin tumor; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008233; MedGen: C0031511; Orphanet: 29072; OMIM: 171300; Human Phenotype Ontology: HP:0002666
Name:
Paragangliomas 1 (PGL1)
Synonyms:
PARAGANGLIOMA, CAROTID BODY; PARAGANGLIOMAS, FAMILIAL NONCHROMAFFIN, 1; PGL 1; See all synonyms [MedGen]
Identifiers:
MedGen: C1868633; Orphanet: 29072; OMIM: 168000
Name:
Cowden syndrome 3 (CWS3)
Identifiers:
MONDO: MONDO:0014045; MedGen: CN166604; Orphanet: 201

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000823357Invitaecriteria provided, single submitter
Pathogenic
(Oct 3, 2020)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot 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

Paraganglioma of the carotid body: treatment strategy and SDH-gene mutations.

Fruhmann J, Geigl JB, Konstantiniuk P, Cohnert TU.

Eur J Vasc Endovasc Surg. 2013 May;45(5):431-6. doi: 10.1016/j.ejvs.2013.01.018. Epub 2013 Feb 19.

PubMed [citation]
PMID:
23433498
See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000823357.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This sequence change replaces tyrosine with cysteine at codon 114 of the SDHD protein (p.Tyr114Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals and families affected with pheochromocytomas and paragangliomas (PMID: 22456618, 11343322, 23433498, 27279923, 16317055, 29386252), and has been reported to segregate with disease in several families (PMID: 17563904, 16080474, 25275255). This variant is also described as a founder mutation of the Trentino area in Italy (PMID: 22456618). ClinVar contains an entry for this variant (Variation ID: 6900). Experimental studies have shown that this missense change causes severe functional defect with oxidative growth inability and increased mitochondrial DNA mutability in yeast complementation assay (PMID: 23175444). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Nov 20, 2021

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