NM_003000.3(SDHB):c.127G>C (p.Ala43Pro) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 27, 2022
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:: RCV003094846.4

Allele description [Variation Report for NM_003000.3(SDHB):c.127G>C (p.Ala43Pro)]

NM_003000.3(SDHB):c.127G>C (p.Ala43Pro)

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.127G>C (p.Ala43Pro)

HGVS:

NC_000001.11:g.17044834C>G
NG_012340.1:g.14337G>C
NM_001407361.1:c.127G>C
NM_003000.3:c.127G>CMANE SELECT
NP_001394290.1:p.Ala43Pro
NP_002991.2:p.Ala43Pro
NP_002991.2:p.Ala43Pro
LRG_316t1:c.127G>C
LRG_316:g.14337G>C
LRG_316p1:p.Ala43Pro
NC_000001.10:g.17371329C>G
NM_003000.2:c.127G>C

Protein change:

A43P

Molecular consequence:

NM_001407361.1:c.127G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003000.3:c.127G>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003522748	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 27, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22835832, 25972245, 14500403, 19454582, 22492777, 24092654, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003522748

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 27, 2022)

germline

clinical testing

PubMed (7)
[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

Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function.

Yang C, Matro JC, Huntoon KM, Ye DY, Huynh TT, Fliedner SM, Breza J, Zhuang Z, Pacak K.

FASEB J. 2012 Nov;26(11):4506-16. doi: 10.1096/fj.12-210146. Epub 2012 Jul 26.

PubMed [citation]

PMID:: 22835832
PMCID:: PMC3475262

Structural and functional consequences of succinate dehydrogenase subunit B mutations.

Kim E, Rath EM, Tsang VH, Duff AP, Robinson BG, Church WB, Benn DE, Dwight T, Clifton-Bligh RJ.

Endocr Relat Cancer. 2015 Jun;22(3):387-97. doi: 10.1530/ERC-15-0099.

PubMed [citation]

PMID:: 25972245

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003522748.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832, 25972245). 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. This missense change has been observed in individuals with paragangliomas and/or phaeochromocytomas (PMID: 14500403, 19454582, 22492777, 24092654). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 43 of the SDHB protein (p.Ala43Pro).

#	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: Sep 29, 2024

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