NM_003000.3(SDHB):c.136C>T (p.Arg46Ter) AND Hereditary pheochromocytoma-paraganglioma

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 5, 2024
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:: RCV000505277.4

Allele description [Variation Report for NM_003000.3(SDHB):c.136C>T (p.Arg46Ter)]

NM_003000.3(SDHB):c.136C>T (p.Arg46Ter)

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.136C>T (p.Arg46Ter)

Other names:

p.R46*:CGA>TGA

HGVS:

NC_000001.11:g.17044825G>A
NG_012340.1:g.14346C>T
NM_003000.3:c.136C>TMANE SELECT
NP_002991.2:p.Arg46Ter
NP_002991.2:p.Arg46Ter
LRG_316t1:c.136C>T
LRG_316:g.14346C>T
LRG_316p1:p.Arg46Ter
NC_000001.10:g.17371320G>A
NM_003000.2:c.136C>T
p.R46*

Protein change:

R46*

Links:

dbSNP: rs74315370

NCBI 1000 Genomes Browser:

rs74315370

Molecular consequence:

NM_003000.3:c.136C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000599486	Section on Medical Neuroendocrinolgy, National Institutes of Health	no assertion criteria provided	Pathogenic	germline	research
SCV004821944	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 5, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 19075037, 19454582, 21348866, 21909610, 23797725, 27539324, 28944243, 30122763, 25741868
SCV004847568	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 10, 2020)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 21348866, 18728283, 30050099, 27539324, 23797725, 18419787, 19075037, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000599486

Section on Medical Neuroendocrinolgy, National Institutes of Health

no assertion criteria provided

Pathogenic

germline

research

SCV004821944

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 5, 2024)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV004847568

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 10, 2020)

germline

clinical testing

PubMed (8)
[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	3	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas.

Burnichon N, Rohmer V, Amar L, Herman P, Leboulleux S, Darrouzet V, Niccoli P, Gaillard D, Chabrier G, Chabolle F, Coupier I, Thieblot P, Lecomte P, Bertherat J, Wion-Barbot N, Murat A, Venisse A, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP; PGL.NET network..

J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27. doi: 10.1210/jc.2008-2504. Epub 2009 May 19.

PubMed [citation]

PMID:: 19454582

[The mutations of germline succinate dehydrogrnase subunit B (SDHB) in sporadic paragangliomas].

Zu TJ, Jia MY, Yuan RT, Bu LX, Yao RY.

Shanghai Kou Qiang Yi Xue. 2011 Aug;20(4):413-6. Chinese.

PubMed [citation]

PMID:: 21909610

See all PubMed Citations (12)

Details of each submission

From Section on Medical Neuroendocrinolgy, National Institutes of Health, SCV000599486.1

#	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 All of Us Research Program, National Institutes of Health, SCV004821944.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (9)

Description

This variant changes 1 nucleotide in exon 2 of the SDHB gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with pheochromocytoma/paraganglioma (PMID: 19075037, 19454582, 21348866, 21909610, 23797725, 27539324, 28944243, 30122763). This variant has been identified in 5/282738 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHB function is a known mechanism of disease (clinicalgenome.org). 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		3	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847568.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.Arg46X variant in SDHB has been reported in 11 individuals with SDHB-associated tumors and segregated with disease in 5 affected individuals from 3 families (Ricketts 2008 PMID:18728283, Srirangalingam 2008 PMID:18419787, Ghayee 2009 PMID:19075037, Hensen 2012 PMID:21348866, Mason 2013 PMID:23797725, Pandit 2016 PMID:27539324, Richter 2019 PMID:30050099). It has also been identified in 0.014% (1/7218) of "Other" or 0.008% of Finnish (2/25082) chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 142763). This nonsense variant leads to a premature termination codon at position 46, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SDHB gene is an established disease mechanism in autosomal dominant hereditary paraganglioma and pheochromocytoma. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary paraganglioma and pheochromocytoma. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2_Supporting, PP1_Moderate

#	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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