NM_003000.3(SDHB):c.379A>G (p.Ile127Val) AND multiple conditions

Clinical significance:Uncertain significance (Last evaluated: Aug 20, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001064015.2

Allele description [Variation Report for NM_003000.3(SDHB):c.379A>G (p.Ile127Val)]

NM_003000.3(SDHB):c.379A>G (p.Ile127Val)

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.379A>G (p.Ile127Val)
HGVS:
  • NC_000001.11:g.17028644T>C
  • NG_012340.1:g.30527A>G
  • NM_003000.3:c.379A>GMANE SELECT
  • NP_002991.2:p.Ile127Val
  • LRG_316t1:c.379A>G
  • LRG_316:g.30527A>G
  • NC_000001.10:g.17355139T>C
  • NM_003000.2:c.379A>G
Protein change:
I127V
Molecular consequence:
  • NM_003000.3:c.379A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Gastrointestinal stromal tumor (GIST)
Synonyms:
Gastrointestinal Stromal Sarcoma; Gastrointestinal stromal tumor, somatic; Gastrointestinal stroma tumor; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0011719; MeSH: D046152; MedGen: C0238198; Orphanet: 44890; OMIM: 606764; Human Phenotype Ontology: HP:0100723
Name:
Paragangliomas 4 (PGL4)
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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001228888Invitaecriteria provided, single submitter
Uncertain significance
(Aug 20, 2020)
germlineclinical testing

PubMed (6)
[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

Gastrointestinal stromal tumour in succinate dehydrogenase subunit B mutation-associated familial phaeochromocytoma/paraganglioma.

Bolland M, Benn D, Croxson M, McCall J, Shaw JF, Baillie T, Robinson B.

ANZ J Surg. 2006 Aug;76(8):763-4. No abstract available.

PubMed [citation]
PMID:
16916404

Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations.

Pollard PJ, Brière JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP.

Hum Mol Genet. 2005 Aug 1;14(15):2231-9. Epub 2005 Jun 29.

PubMed [citation]
PMID:
15987702
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001228888.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces isoleucine with valine at codon 127 of the SDHB protein (p.Ile127Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SDHB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Ile127 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16916404, 15987702, 19802898, 21820839, 25972245). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 7, 2021

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