rs397516836

chr1-17024015-C-Achr1-17024015-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_003000.3(SDHB):c.600G>T(p.Trp200Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,960 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. W200R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• 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 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_003000.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-17024017-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 571856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 1-17024015-C-A is Pathogenic according to our data. Variant chr1-17024015-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17024015-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.600G>T	p.Trp200Cys	missense_variant	6/8	ENST00000375499.8
SDHB	NM_001407361.1	c.546G>T	p.Trp182Cys	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.600G>T	p.Trp200Cys	missense_variant	6/8	1	NM_003000.3	P1
SDHB	ENST00000491274.6	c.558G>T	p.Trp186Cys	missense_variant	6/8	5
SDHB	ENST00000463045.3	c.429G>T	p.Trp143Cys	missense_variant	6/8	3
SDHB	ENST00000485515.5	n.534G>T		non_coding_transcript_exon_variant	6/7	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727164

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: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000996 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:4

Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2021	Variant summary: SDHB c.600G>T (p.Trp200Cys) results in a non-conservative amino acid change located in the 4E-4S ferredoxin type, iron-sulfur binding domain (IPR017896) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251310 control chromosomes. c.600G>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Drucker_2006, Timmers_2007, Klein_2008, Ricketts_2010, Alrashdi_2010, Greenberg_2020) and in at-least one report of an individual with gastrointestinal stromal tumor (GIST) who lacked mutations in KIT or PDGFRA (example, Janeway_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a dramatically reduced half-life reflective of increased protein degradation (example, Yang_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 10, 2023	This missense variant replaces tryptophan with cysteine at codon 200 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 significantly reduces SDHB protein stability (PMID: 22835832). This variant has been reported in individuals affected with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, head and neck paragangliomas, and in individuals with Carney triad syndrome (PMID: 17143317, 17200167, 18382370, 19184535, 19802898, 20119652, 32741965). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 09, 2023	The p.Trp200Cys variant in SDHB has been reported in over 15 individuals with paragangliomas or pheochromocytomas and segregated with disease in 1 affected relative (Timmers 2007 PMID: 17200167, Klein 2008 PMID: 18382370, Henderson 2009 PMID: 19184535, Alrashdi 2010 PMID: 20119652, Lodish 2010 PMID: 20418362, Janeway 2011 PMID: 21173220, Daniel 2016 PMID: 26173966, Andrews 2018 PMID: 29386252, Greenberg 2020 PMID: 32741965). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183747) and has been identified in 0.002% (1/41452) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). In vitro functional studies provide some evidence that this variant impacts protein stability (Yang 2012 PMID: 22835832) and computational prediction tools and conservation analysis suggest that this variant may impact the protein. Another variant involving this codon (p.Trp200Arg) has been identified in individuals with hereditary paraganglioma/pheochromocytoma syndrome (Heller 2010 PMID: 26273102) and is classified as likely pathogenic in ClinVar (variation ID: 571856). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary paraganglioma/pheochromocytoma syndrome. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PS3_Supporting, PP3. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2023	The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with paraganglioma-pheochromocytoma syndrome. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 22835832) -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2023	Published functional studies demonstrate a damaging effect: results in an unstable protein and impairs binding with SDHAF1 (Yang et al., 2012; Maio et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17200167, 27812541, 18840642, 19286091, 18382370, 20418362, 20119652, 28374168, 19184535, 26173966, 25371406, 21173220, 19802898, 25394176, 27011036, 23282968, 17143317, 27006389, 26749241, 29386252, 28152038, 30949620, 32741965, 33087929, 34906457, 34308366, 35668420, 34703596, 28873162, 32062700, 35060925, 35441217, 34095481, Rutkowski2022[article], 22835832) -

Paragangliomas 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 08, 2024	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17143317, 21173220, 19184535, 32741965]. Functional studies indicate this variant impacts protein function [PMID: 22835832]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 200 of the SDHB protein (p.Trp200Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paragangliomas (PMID: 17143317, 17200167, 18382370, 19184535, 19802898, 20119652, 21173220). ClinVar contains an entry for this variant (Variation ID: 183747). 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. -

Gastrointestinal stromal tumor Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 16, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2022

The p.W200C pathogenic mutation (also known as c.600G>T), located in coding exon 6 of the SDHB gene, results from a G to T substitution at nucleotide position 600. The tryptophan at codon 200 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been detected in multiple individuals with paragangliomas (PGL), pheochromocytomas (PCC), gastrointestinal stromal tumors (GIST), other tumors associated with hereditary PGL-PCC syndrome, and has also been implicated in Carney triad (Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar;92(3):779-786; Lodish MB et al. Endocr. Relat. Cancer. 2010 Sep;17(3):581-8; Drucker AM and Houlden RL. Nature Clin. Pract. Endocrinol. & Metab. 2006 Dec;2(12):702-6; Henderson A et al. Fam. Cancer 2009 Jan;8(3):257-60; Alrashdi I et al. Fam Cancer 2010 Sep;9(3):443-447; Janeway KA et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Jan;108(1):314-8; Andrews KA et al. J. Med. Genet. 2018 Jan; Boikos SA et al. Eur. J. Hum. Genet. 2016 Apr;24(4):569-73). In addition to the clinical data presented in the literature, functional studies demonstrated rapid and significant loss of W200C mutant SDHB protein compared to wildtype in a protein stability cell based assay (Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). 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	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-12	D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.86		Gain of catalytic residue at W201 (P = 0.0222);.;
MVP		0.98
MPC		0.86
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.96

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: rs397516836; hg19: chr1-17350510;