NM_003000.3(SDHB):c.137G>A (p.Arg46Gln) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 1, 2022
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:: RCV000183217.31

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000235637	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 8, 2021)	germline	clinical testing	Citation Link,
SCV000886095	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Mar 1, 2018)	germline	clinical testing	Citation Link,
SCV002496465	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jan 1, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000235637

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 8, 2021)

germline

clinical testing

Citation Link,

SCV000886095

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Mar 1, 2018)

germline

clinical testing

Citation Link,

SCV002496465

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Jan 1, 2022)

germline

clinical testing

Citation Link

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
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000235637.15

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

Description

Published functional studies demonstrate a damaging effect: reduced protein stability, decreased succinate dehydrogenase activity, and increased hypoxia-inducible factors (Giminez-Roqueplo et al., 2002; Yang et al., 2012; Saxena et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18728283, 23083876, 15987702, 24659481, 28738844, 24102379, 31447099, 12364472, 26464466, 15476441, 22835832, 19454582, 12618761, 16317055, 17102082, 23512077, 14500403, 23282968, 23175444, 19522823, 18362451, 18840642, 19576851, 16314641, 26719882, 28374168, 27700540, 25972245, 28503760, 28944243, 29386252, 28152038, 29951630, 30487145, 30877234, 28490599, 30122538, 30694796, 31492822, 32741965)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000886095.1

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

Description

The SDHB c.137G>A; p.Arg46Gln variant (rs772551056) has been observed in individuals and families affected with pheochromocytoma, paraganglioma, adrenal tumors, and renal cell carcinoma (Benn 2003, Gimenez-Roqueplo 2003, Neumann 2004, Ricketts 2012). This variant has been reported as pathogenic by several laboratories in ClinVar (Variation ID: 183793) and has been observed in the general population at a low overall frequency of 0.0004% (1/246124 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (p.Arg46Gly) has been observed in individuals affected with extra-adrenal pheochromocytoma and adrenal tumors and is considered pathogenic (Gimenez-Roqueplo 2003, Neumann 2004). The arginine at codon 46 is highly conserved and computational algorithms (SIFT, PolyPhen-2) predict this variant to be deleterious. Further, functional analyses of p.Arg46Gln demonstrate decreased succinate dehydrogenase expression and activity and increased hypoxia-inducible factors (Saxena 2016). Based on the above information, this variant is considered pathogenic. References: Benn D et al. Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas. Oncogene. 2003 Mar 6;22(9):1358-64. Gimenez-Roqueplo A et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003 Sep 1;63(17):5615-21. Neumann H et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. Ricketts C et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol. 2012 Dec;188(6):2063-71. Saxena N et al. SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. J Natl Cancer Inst. 2016 Jan; 108(1): djv287.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV002496465.18

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

Last Updated: Oct 20, 2024

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