rs876658367

Positions:

• chr1-17024028-C-T

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.587G>A​(p.Cys196Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,690 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C196R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.08

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 6 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 chr1-17024029-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1498117.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 1-17024028-C-T is Pathogenic according to our data. Variant chr1-17024028-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 230070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17024028-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.587G>A	p.Cys196Tyr	missense_variant	6/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.533G>A	p.Cys178Tyr	missense_variant	6/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.587G>A	p.Cys196Tyr	missense_variant	6/8	1	NM_003000.3	ENSP00000364649.3
SDHB	ENST00000491274.6	c.545G>A	p.Cys182Tyr	missense_variant	6/8	5		ENSP00000480482.2
SDHB	ENST00000463045.3	c.416G>A	p.Cys139Tyr	missense_variant	6/8	3		ENSP00000481376.2
SDHB	ENST00000485515.5	n.521G>A		non_coding_transcript_exon_variant	6/7	5		ENSP00000519322.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461690 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727140

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paragangliomas 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 07, 2023	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 26259135, 19576851, 28374168, 31492822, 35060925]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 196 of the SDHB protein (p.Cys196Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pheochromocytomas (PCC) and/or paragangliomas (PGL) many of whom had malignant tumors or family members affected with PCC or PGL (PMID: 17652212, 19064958, 21172883, 23666964, 24781345, 25683602). ClinVar contains an entry for this variant (Variation ID: 230070). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 03, 2018

This pathogenic variant is denoted SDHB c.587G>A at the cDNA level, p.Cys196Tyr (C196Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant has been observed in several individuals and families with both malignant and non-malignant paragangliomas/pheochromocytomas, with at least one tumor showing loss of SDHB protein expression via immunohistochemistry (Neumann 2002, Brouwers 2006, Timmers 2008, Burnichon 2009, Hahn 2009, Dubb 2014, Renella 2014, Michalowska 2015, Jochmanova 2017). Cells transfected with SDHB Cys196Tyr demonstrated SDHB protein loss due to a reduced half-life of the variant protein (Yang 2012). SDHB Cys196Tyr was not observed in large population cohorts (Lek 2016). SDHB Cys196Tyr is located in the 4Fe-4S ferredoxin-type domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. 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

Dec 23, 2021

The p.C196Y pathogenic mutation (also known as c.587G>A), located in coding exon 6 of the SDHB gene, results from a G to A substitution at nucleotide position 587. The cysteine at codon 196 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation is in the 4Fe-4S ferredoxin-type domain and has been reported in numerous patients with a pheochromocytoma and/or paraganglioma (Neumann HP et al. N. Engl. J. Med. 2002 May; 346(19):1459-66; Amar L et al. J. Clin. Oncol. 2005 Dec; 23(34):8812-8; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar; 91(3):827-36; Brouwers FM et al. J. Clin. Endocrinol. Metab. 2006 Nov; 91(11):4505-9; Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar; 92(3):779-86; Amar L et al. J. Clin. Endocrinol. Metab. 2007 Oct; 92(10):3822-8; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug; 94(8):2817-27; Renella R et al. Fam. Cancer. 2014 Sep;13(3):507-11; Tufton N et al. Endocr. Pathol. 2017 Dec;28(4):320-325). A functional study investigating SDHB missense mutations demonstrated that this variant was associated with accelerated protein degradation and consequent functional insufficiency of the protein (Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). Of note, this alteration is also referred to as c.721G>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

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	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.4	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-9.9	D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.94		Loss of glycosylation at S195 (P = 0.2554);.;
MVP		1.0
MPC		0.92
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: rs876658367; hg19: chr1-17350523;