rs786202732

chr1-17024041-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003000.3(SDHB):c.574T>C(p.Cys192Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C192S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.36

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr1-17024040-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 142047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 1-17024041-A-G is Pathogenic according to our data. Variant chr1-17024041-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 186150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17024041-A-G is described in Lovd as [Likely_pathogenic]. Variant chr1-17024041-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.574T>C	p.Cys192Arg	missense_variant	6/8	ENST00000375499.8
SDHB	NM_001407361.1	c.520T>C	p.Cys174Arg	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.574T>C	p.Cys192Arg	missense_variant	6/8	1	NM_003000.3	P1
SDHB	ENST00000491274.6	c.532T>C	p.Cys178Arg	missense_variant	6/8	5
SDHB	ENST00000463045.3	c.403T>C	p.Cys135Arg	missense_variant	6/8	3
SDHB	ENST00000485515.5	n.508T>C		non_coding_transcript_exon_variant	6/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461668 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 192 of the SDHB protein (p.Cys192Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paragangliomas and/or pheochromocytomas many of them were classified as malignant (PMID: 12000816, 17200167, 18382370, 22517554, 25371406, 27785149). ClinVar contains an entry for this variant (Variation ID: 186150). 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). For these reasons, this variant has been classified as Pathogenic. -

Paragangliomas 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 08, 2023

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:33628464, 30050099, 27867439, 28503760]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 04, 2016

This pathogenic variant is denoted SDHB c.574T>C at the cDNA level, p.Cys192Arg (C192R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has been reported in numerous individuals with parangangliomas or pheochromocytomas, many of which were metastatic (Neumann 2002, Timmers 2007, Burnichon 2009, Hensen 2012, Lefebvre 2012, Michalowska 2015, Sue 2015). SDHB Cys192Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHB Cys192Arg occurs at a position that is conserved across species and is located in the 4Fe-4S ferredoxin-type domain (Uniprot). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2022

The p.C192R pathogenic mutation (also known as c.574T>C), located in coding exon 6 of the SDHB gene, results from a T to C substitution at nucleotide position 574. The cysteine at codon 192 is replaced by arginine, an amino acid with highly dissimilar properties.This alteration has been identified in numerous individuals with paragangliomas and pheochromocytomas (Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Lefebvre S et al. Horm. Metab. Res. 2012 May;44(5):334-8; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27; Klein RD et al. Diagn. Mol. Pathol. 2008 Jun;17(2):94-100; Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar; 92(3):779-86; Michaowska I et al. Kardiochir Torakochirurgia Pol, 2016 Sep;13:276-282). In one series of functional studies, the SDHB p.C192R mutant protein was subject to premature degradation, possibly due to the increased ubiquitination levels observed in the mutant protein compared to wild type SDHB protein (Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). The Cys192 residue plays a vital role coordinating the Fe4S4 cluster and it is believed that alterations at this location would prevent assembly of Complex II (Iverson TM et al. J. Biol. Chem. 2012 Oct;287(42):35430-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Section on Medical Neuroendocrinolgy, National Institutes of Health

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Pathogenic	4.2	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-11	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.97		Loss of catalytic residue at C191 (P = 0.1088);.;
MVP		1.0
MPC		0.94
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.99

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

Other links and lift over

dbSNP: rs786202732; hg19: chr1-17350536;