NM_003000.3(SDHB):c.137G>A (p.Arg46Gln) AND Hereditary pheochromocytoma-paraganglioma

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000505310.13

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]

Observations:

Condition(s)

Name:: Hereditary pheochromocytoma-paraganglioma
Synonyms:: Hereditary Paraganglioma-Pheochromocytoma Syndromes; Hereditary Paragangliomas and Pheochromocytomas
Identifiers:: MONDO: MONDO:0017366; MedGen: C1708353

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000599484	Section on Medical Neuroendocrinolgy, National Institutes of Health	no assertion criteria provided	Pathogenic	germline	research
SCV000712031	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 29, 2020)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 12364472, 12618761, 16314641, 25972245, 17102082, 18362451, 23083876, 24659481, 26719882, 25741868
SCV004821943	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 11, 2023)	germline	clinical testing	PubMed (29) [See all records that cite these PMIDs] 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 22835832, 23083876, 23175444, 23282968, 23512077, 24102379, 24606901, 24659481, 25972245, 26719882, 28374168, 28503760, 28738844, 29386252, 29951630, 31492822, 32741965, 32963463, 34439168, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000599484

Section on Medical Neuroendocrinolgy, National Institutes of Health

no assertion criteria provided

Pathogenic

germline

research

SCV000712031

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 29, 2020)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV004821943

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 11, 2023)

germline

clinical testing

PubMed (29)
[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	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma.

Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rötig A, Jeunemaitre X.

J Clin Endocrinol Metab. 2002 Oct;87(10):4771-4.

PubMed [citation]

PMID:: 12364472

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

See all PubMed Citations (29)

Details of each submission

From Section on Medical Neuroendocrinolgy, National Institutes of Health, SCV000599484.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712031.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	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

From All of Us Research Program, National Institutes of Health, SCV004821943.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (29)

Description

This missense variant replaces arginine with glutamine at codon 46 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and/or pheochromocytoma (PMID: 12364472, 12618761, 14500403, 15328326, 16314641, 16317055, 17102082, 18362451, 18840642, 23512077, 24102379, 24659481, 28374168, 28503760, 29386252, 29951630, 31492822, 32741965, 34439168), and observed in individuals affected with gastrointestinal stromal tumors (GIST; PMID: 23282968), renal cell carcinoma (RCC; PMID: 23083876) and gastric adenocarcinoma (PMID: 32963463). This variant has been identified in 1/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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