NM_003002.4(SDHD):c.342T>A (p.Tyr114Ter) AND multiple conditions

Clinical significance:Pathogenic (Last evaluated: Aug 7, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000546525.2

Allele description [Variation Report for NM_003002.4(SDHD):c.342T>A (p.Tyr114Ter)]

NM_003002.4(SDHD):c.342T>A (p.Tyr114Ter)

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.342T>A (p.Tyr114Ter)
HGVS:
  • NC_000011.10:g.112094832T>A
  • NG_012337.3:g.12986T>A
  • NM_001276503.2:c.197T>A
  • NM_001276504.2:c.225T>A
  • NM_001276506.2:c.*40T>A
  • NM_003002.4:c.342T>AMANE SELECT
  • NP_001263432.1:p.Met66Lys
  • NP_001263433.1:p.Tyr75Ter
  • NP_002993.1:p.Tyr114Ter
  • LRG_9t1:c.342T>A
  • LRG_9:g.12986T>A
  • LRG_9p1:p.Tyr114Ter
  • NC_000011.9:g.111965556T>A
  • NM_003002.3:c.342T>A
  • NR_077060.2:n.431T>A
Protein change:
M66K
Links:
dbSNP: rs1050032491
NCBI 1000 Genomes Browser:
rs1050032491
Molecular consequence:
  • NM_001276506.2:c.*40T>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001276503.2:c.197T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_077060.2:n.431T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_001276504.2:c.225T>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_003002.4:c.342T>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000645370Invitaecriteria provided, single submitter
Pathogenic
(Aug 7, 2017)
germlineclinical testing

PubMed (4)
[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

Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene.

Taschner PE, Jansen JC, Baysal BE, Bosch A, Rosenberg EH, Bröcker-Vriends AH, van Der Mey AG, van Ommen GJ, Cornelisse CJ, Devilee P.

Genes Chromosomes Cancer. 2001 Jul;31(3):274-81.

PubMed [citation]
PMID:
11391798

High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands.

Hensen EF, van Duinen N, Jansen JC, Corssmit EP, Tops CM, Romijn JA, Vriends AH, van der Mey AG, Cornelisse CJ, Devilee P, Bayley JP.

Clin Genet. 2012 Mar;81(3):284-8. doi: 10.1111/j.1399-0004.2011.01653.x. Epub 2011 Mar 15.

PubMed [citation]
PMID:
21348866
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000645370.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change results in a premature translational stop signal in the last exon of the SDHD mRNA at codon 114 (p.Tyr114*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 46 amino acids of the SDHD protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with SDHD-related malignant paragangliomas (PMID: 17973943). While no functional studies have been performed to test the effects of this particular variant on SDHD protein function or stability, it deletes 46 C-terminal amino acid residues from the SDHD protein. A founder mutation (p.Leu139Pro) has been reported in this region (PMID: 21348866, 11391798), indicating that the C-terminal amino acid residues may be critical for SDHD function. In summary, this is a rare truncating variant that is expected to disrupt 46 C-terminal amino acids of the SDHD protein, including a region shown to be critical for SDHD protein function. In addition, this variant is absent in the population, and has been reported in an affected individual. 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 27, 2021

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