rs786201083

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_003000.3(SDHB):c.137G>A(p.Arg46Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,613,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SDHB
NM_003000.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 7.14

Variant links:

Genes affected

SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]

SDHB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_003000.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-17044825-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 1-17044824-C-T is Pathogenic according to our data. Variant chr1-17044824-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17044824-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3 link	c.137G>A	p.Arg46Gln	missense_variant	Exon 2 of 8	ENST00000375499.8	NP_002991.2	P21912
SDHB	NM_001407361.1 link	c.137G>A	p.Arg46Gln	missense_variant	Exon 2 of 8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8 link	c.137G>A	p.Arg46Gln	missense_variant	Exon 2 of 8	1	NM_003000.3	ENSP00000364649.3		P21912

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251358

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paragangliomas 4

Pathogenic:5

Aug 09, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 02, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22677546, 26719882, 25972245]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12618761, 28374168, 23512077, 34439168]. -

Jun 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Pathogenic:4

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP4, PM2_moderate, PS3_supporting, PS4_moderate -

Mar 08, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 01, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:3

Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 29, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Mar 24, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SDHB-related disorder

Pathogenic:2

Jan 01, 2017

Snyder Lab, Genetics Department, Stanford University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SDHB c.137G>A variant is predicted to result in the amino acid substitution p.Arg46Gln. This variant has been reported in several unrelated individuals with pheochromocytoma, paraganglioma, and gastrointestinal stromal tumors (see for example, Gimenez-Roqueplo et al. 2002. PubMed ID: 12364472; Gimenez-Roqueplo et al. 2003. PubMed ID: 14500403 Benn et al. 2003. PubMed ID: 12618761; Neumann et al. 2004. PubMed ID: 15328326; Miettinen et al. 2013. PubMed ID: 23282968). Functional in vitro assays show that this variant leads to protein instability (Yang et al. 2012. PubMed ID: 22835832; Saxena et al. 2016. PubMed ID: 26719882). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, it is reported as likely pathogenic/pathogenic by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/183793/). We classify this variant as pathogenic. -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1861848:Paragangliomas 4

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma

Pathogenic:1

Feb 28, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4

Pathogenic:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the SDHB protein (p.Arg46Gln). This variant is present in population databases (rs772551056, gnomAD 0.0009%). This missense change has been observed in individuals with pheochromocytoma, paraganglioma, gastrointestinal stromal tumors, adrenal tumors, and renal cancer (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968). ClinVar contains an entry for this variant (Variation ID: 183793). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832, 25972245, 26719882). This variant disrupts the p.Arg46 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14500403, 15328326, 25972245). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Gastrointestinal stromal tumor

Pathogenic:1

Nov 08, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Dec 08, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R46Q pathogenic mutation (also known as c.137G>A), located in coding exon 2 of the SDHB gene, results from a G to A substitution at nucleotide position 137. The arginine at codon 46 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been seen in multiple patients with pheochromocytoma, paraganglioma, and/or GIST (Gimenez-Roqueplo AP et al. J. Clin. Endocrinol. Metab. 2002 Oct;87:4771-4; Benn DE et al. Oncogene, 2003 Mar;22:1358-64; Neumann HP et al. JAMA, 2004 Aug;292:943-51; Benn DE et al. J Clin Endocrinol Metab, 2006 Mar;91:827-36; Timmers HJ et al. J Clin Endocrinol Metab, 2008 Dec;93:4826-32; Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40; McInerney-Leo AM et al. Clin Endocrinol (Oxf), 2014 Jan;80:25-33; Kimura N et al. Endocr Relat Cancer, 2014 Jun;21:L13-6; Rijken JA et al. Clin. Genet. 2017 May; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394; Ji K et al. Chin J Cancer Res, 2020 Aug;32:508-515; Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Bayley JP et al. J Med Genet, 2020 02;57:96-103; Yonamine M et al. Cancers (Basel), 2021 Aug;13). This mutation has been shown to increase protein degradation and to reduce mutant protein half-life in transfected cell lines (Saxena N et al. J. Natl. Cancer Inst. 2016 Jan;108; Yang C et al. FASEB J, 2012 Nov;26:4506-16). In addition, in vitro analyses have shown significantly reduced mitochondrial SDHB expression and a reduction in SDHB enzymatic activity compared to wild type (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Functional analysis of R46Q demonstrated complete loss of SDHB-SDHAF3 interaction (Dwight T et al. BMC Cancer, 2017 Jul;17:497). Structural analysis showed that the R46Q alteration impaired iron incorporation and Complex II biogenesis (Maio N et al. Cell Metab, 2014 Mar;19:445-57). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.6

H;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.3

D;.

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.97

MutPred

0.94

Loss of MoRF binding (P = 0.0347);.;

MVP

0.99

MPC

0.75

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over