chr1-17024015-C-A

Variant names:

• chr1-17024015-C-A
• rs397516836
• NM_003000.3:c.600G>T
• SDHB p.Trp200Cys

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 15 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPM5PP3_ModeratePP5_Strong

The NM_003000.3(SDHB):c.600G>T (p.Trp200Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000682 (AC=11) in the gnomAD database across 1,613,960 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000241. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000212817: 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)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.W200R: Likely_pathogenic (ClinVar VariationId 571856, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.W200G: Uncertain_significance (ClinVar VariationId 2942599, 1 star)

• 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:17
• Conservation: PhyloP100: 7.08
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• Carney-Stratakis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 15 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000212817: 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).; SCV000554005: Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832).; SCV001519621: The most pronounced variant effect results in a dramatically reduced half-life reflective of increased protein degradation (example, Yang_2012).; SCV004821940: Functional studies have shown that this variant significantly reduces SDHB protein stability (PMID: 22835832).; SCV004847569: In vitro functional studies provide some evidence that this variant impacts protein stability (Yang 2012 PMID: 22835832).; SCV004933753: Functional studies indicate this variant impacts protein function [PMID: 22835832].; SCV001805236: 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); SCV004230023: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 22835832)
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 121 pathogenic, 13 benign rare missense variants (OR vs. background: 45.0).; ±8 AA neighbourhood: 13 pathogenic, 0 benign (OR vs. background: 135.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000241 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.W200R: Likely_pathogenic (ClinVar VariationId 571856, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.W200G: Uncertain_significance (ClinVar VariationId 2942599, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (17/17 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_003000.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SDHB NM_003000.3	MANE Select	c.600G>T p.Trp200Cys	missense	Exon 6 of 8	Prot: NP_002991.2 UniProt:
	SDHB NM_001407361.1		c.546G>T p.Trp182Cys	missense	Exon 6 of 8	Prot: NP_001394290.1 UniProt:

SDHB NM_003000.3

MANE Select

HGVSc / HGVSpc.600G>Tp.Trp200Cys

Exon rankExon 6 of 8

missense

Prot: NP_002991.2UniProt: P21912

SDHB NM_001407361.1

HGVSc / HGVSpc.546G>Tp.Trp182Cys

Exon rankExon 6 of 8

missense

Prot: NP_001394290.1UniProt: A0AAQ5BHD9

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SDHB ENST00000375499.8	TSL:1MANE Select	c.600G>T p.Trp200Cys	missense	Exon 6 of 8	Prot: ENSP00000364649.3 UniProt:
	SDHB ENST00000714034.1		c.645G>T p.Trp215Cys	missense	Exon 7 of 9	Prot: ENSP00000519325.1 UniProt:
	SDHB ENST00000925621.1		c.594G>T p.Trp198Cys	missense	Exon 6 of 8	Prot: ENSP00000595680.1 UniProt:

SDHB ENST00000375499.8

TSL:1MANE Select

HGVSc / HGVSpc.600G>Tp.Trp200Cys

Exon rankExon 6 of 8

missense

Prot: ENSP00000364649.3UniProt: P21912

SDHB ENST00000714034.1

HGVSc / HGVSpc.645G>Tp.Trp215Cys

Exon rankExon 7 of 9

missense

Prot: ENSP00000519325.1UniProt: A0AAQ5BHC9

SDHB ENST00000925621.1

HGVSc / HGVSpc.594G>Tp.Trp198Cys

Exon rankExon 6 of 8

missense

Prot: ENSP00000595680.1UniProt: A0ACI8TBD9

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152212	Cov:33
GnomAD4 exome	AF: 0.00000684	AC:10	Hom:0	AN:1461748	Cov:31
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152212	Cov:33
TOPMed (Bravo)	AF: 0.0000113	AC:3	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000640	AC:4	Hom:0	AN:62496	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.00000968	1	103272	0.00	0	184440

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Hereditary pheochromocytoma and paraganglioma (5)
4	-	-	not provided (4)
2	-	-	Inherited phaeochromocytoma and paraganglioma excluding NF1 (2)
2	-	-	Pheochromocytoma/paraganglioma syndrome 4 (2)
1	-	-	Gastrointestinal stromal tumor (1)
1	-	-	Gastrointestinal stromal tumor;C1847319:Carney-Stratakis syndrome;C1861848:Pheochromocytoma/paraganglioma syndrome 4;C5543176:Mitochondrial complex 2 deficiency, nuclear type 4 (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	32
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
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.1	H
PhyloP100	Uncertain	7.1
popEVE	Benign	-4.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.99
VESM-3B	Benign	-13

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs397516836;

hg19: chr1-17350510;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar