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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 6, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002524416.9

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_003002.2:c.342T>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 with sensorineural hearing loss (PGL1)
Identifiers:: MedGen: C1868633

Name:: Cowden syndrome 3 (CWS3)
Identifiers:: MONDO: MONDO:0014045; MedGen: CN166604; Orphanet: 201

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000645370	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 6, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21348866, 11391798, 17973943, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000645370

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 6, 2017)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000645370.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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. 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. 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. This variant has been reported in an individual affected with SDHD-related malignant paragangliomas (PMID: 17973943). This variant is not present in population databases (ExAC no frequency).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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