rs138996609

Positions:

chr1-17022685-G-A

Variant summary

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

The NM_003000.3(SDHB):c.688C>T(p.Arg230Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,896 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. R230H) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SDHB
NM_003000.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.98

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:

SDHB (HGNC:):

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 chain Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial (size 251) in uniprot entity SDHB_HUMAN there are 195 pathogenic changes around while only 17 benign (92%) 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 chr1-17022684-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 1-17022685-G-A is Pathogenic according to our data. Variant chr1-17022685-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17022685-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3 linkuse as main transcript	c.688C>T	p.Arg230Cys	missense_variant	7/8	ENST00000375499.8	NP_002991.2	P21912
SDHB	NM_001407361.1 linkuse as main transcript	c.634C>T	p.Arg212Cys	missense_variant	7/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8 linkuse as main transcript	c.688C>T	p.Arg230Cys	missense_variant	7/8	1	NM_003000.3	ENSP00000364649.3		P21912

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251398

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

0.00000205

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paragangliomas 4

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 06, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 14, 2018	The c.688C>T (p.Arg230Cys) variant in the SDHB gene has been reported in several unrelated individuals with pheochromocytoma or paraganglioma (PMID: 14500403, 24939699, 20208144, and 28374168). Functional assays have demonstrated that this missense change results in an unstable protein, and in the tumor of an individual with this variant complete and selective loss of mitochondrial complex II enzyme activity was observed (PMID: 22835832, 14500403). Additionally, two other pathogenic/likely pathogenic missense substitutions at this codon have been reported (PMID: 22835832, 23934599, 18382370, and 19351833,) suggesting that the Arg230 residue is critical for normal functioning of the SDHB protein. In light of the currently available data this variant in the SDHB gene is classified pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 08, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 14500403, 33362715, 28374168, 34906457]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 08, 2023	This missense variant replaces arginine with cysteine at codon 230 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 may impact protein stability and increase SDHB ubiquitination (PMID: 14500403, 22835832, 35673401). This variant has been reported in individuals affected with pheochromocytomas, paragangliomas, and gastrointestinal stromal tumors (PMID: 16103922, 17652212, 19351833, 19454582, 20208144, 22517554, 25873086, 29386252, 30536464, 34906457, 33420946, 35673401, 35904169). Other amino acid changes at this codon are considered disease causing (R230L, R230H, R230G; ClinVar Variant IDs: 184933, 142637, 1755980). This variant has been identified in 2/251398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 230 of the SDHB protein (p.Arg230Cys). This variant is present in population databases (rs138996609, gnomAD 0.0009%). This missense change has been observed in individuals with malignant or non-malignant pheochromocytoma or paraganglioma (PMID: 14500403, 17652212, 19454582, 20208144, 22517554, 25873086). ClinVar contains an entry for this variant (Variation ID: 185077). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832). This variant disrupts the p.Arg230 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18382370, 19351833, 23934599; Invitae). 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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2017

This pathogenic variant is denoted SDHB c.688C>T at the cDNA level, p.Arg230Cys (R230C) at theprotein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was observed in severalindividuals with pheochromocytoma or paraganglioma (Gimenez-Roqueplo 2003, Lefebvre 2012, Hermsen 2010,Janssen, Jochmanova 2017). In addition, functional assays have demonstrated this variant to result in an unstableprotein, and in the tumor of an individual harboring this variant, complete and selective loss of mitochondrial complex IIenzyme activity was observed (Yang 2012, Gimenez-Roqueplo 2003). SDHB Arg230Cys was not observed at asignificant allele frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity,charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHB Arg230Cysoccurs at a position that is conserved across species and is not located in a known functional domain. In silicoanalyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currentlyavailable evidence, we consider this variant to be pathogenic -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2022

The p.R230C pathogenic mutation (also known as c.688C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 688. The arginine at codon 230 is replaced by cysteine, an amino acid with highly dissimilar properties. This pathogenic variant has been reported in numerous individuals diagnosed with pheochromocytomas and/or paragangliomas (Gimenez-Roqueplo AP et al. Cancer Res. 2003 Sep 1;63(17):5615-21; Dahia PL et al. PLoS Genet. 2005 Jul;1(1):72-80; Neumann HP et al. Cancer Res. 2009 Apr 15;69(8):3650-6; Sevilla MA et al. Otolaryngol Head Neck Surg. 2009 May;140(5):724-9; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27; Yang C et al. FASEB J. 2012 Nov;26(11):4506-16; Andrews KA et al. J. Med. Genet. 2018 Jun;55:384-394). Additionally, two disease-causing variants, p.R230H and p.R230L, have been described in the same codon. 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

0.96

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MVP

1.0

MPC

0.81

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.95

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