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NM_003000.3(SDHB):c.137G>A (p.Arg46Gln) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 27, 2024
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:
RCV000627748.9

Allele description [Variation Report for NM_003000.3(SDHB):c.137G>A (p.Arg46Gln)]

NM_003000.3(SDHB):c.137G>A (p.Arg46Gln)

Gene:
SDHB:succinate dehydrogenase complex iron sulfur subunit B [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p36.13
Genomic location:
Preferred name:
NM_003000.3(SDHB):c.137G>A (p.Arg46Gln)
Other names:
p.R46Q:CGA>CAA
HGVS:
  • NC_000001.11:g.17044824C>T
  • NG_012340.1:g.14347G>A
  • NM_003000.3:c.137G>AMANE SELECT
  • NP_002991.2:p.Arg46Gln
  • NP_002991.2:p.Arg46Gln
  • LRG_316t1:c.137G>A
  • LRG_316:g.14347G>A
  • LRG_316p1:p.Arg46Gln
  • NC_000001.10:g.17371319C>T
  • NM_003000.2:c.137G>A
  • P21912:p.Arg46Gln
  • p.R46Q
Protein change:
R46Q
Links:
UniProtKB: P21912#VAR_054377; dbSNP: rs772551056
NCBI 1000 Genomes Browser:
rs772551056
Molecular consequence:
  • NM_003000.3:c.137G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Gastrointestinal stromal tumor
Synonyms:
Gastrointestinal Stromal Sarcoma; Gastrointestinal stromal tumor, somatic; Gastrointestinal stroma tumor
Identifiers:
MONDO: MONDO:0011719; MeSH: D046152; MedGen: C0238198; Orphanet: 44890; OMIM: 606764; Human Phenotype Ontology: HP:0100723
Name:
Paragangliomas 4 (PPGL4)
Synonyms:
CAROTID BODY TUMORS AND MULTIPLE EXTRAADRENAL PHEOCHROMOCYTOMAS; Pheochromocytoma, extraadrenal and cervical paraganglioma; Paragangliomas, hereditary extraadrenal; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007273; MedGen: C1861848; Orphanet: 29072; OMIM: 115310
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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000287759Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 27, 2024) 		germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas.

Benn DE, Croxson MS, Tucker K, Bambach CP, Richardson AL, Delbridge L, Pullan PT, Hammond J, Marsh DJ, Robinson BG.

Oncogene. 2003 Mar 6;22(9):1358-64.

PubMed [citation]
PMID:
12618761

Genetic testing in pheochromocytoma or functional paraganglioma.

Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP.

J Clin Oncol. 2005 Dec 1;23(34):8812-8.

PubMed [citation]
PMID:
16314641
See all PubMed Citations (12)

Details of each submission

From Invitae, SCV000287759.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the SDHB protein (p.Arg46Gln). This variant is present in population databases (rs772551056, gnomAD 0.0009%). This missense change has been observed in individuals with pheochromocytoma, paraganglioma, gastrointestinal stromal tumors, adrenal tumors, and renal cancer (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968). ClinVar contains an entry for this variant (Variation ID: 183793). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832, 25972245, 26719882). This variant disrupts the p.Arg46 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14500403, 15328326, 25972245). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: May 12, 2024