SDHB p.Arg46Leu

Variant names:

• chr1-17044824-C-A
• rs772551056
• NM_003000.3:c.137G>T
• SDHB p.Arg46Leu

Your query was ambiguous. Multiple possible variants found:

• chr1-17044824-C-A
• chr1-17044823-TC-AA
• chr1-17044823-TC-CA
• chr1-17044823-TC-GA
• chr1-17044824-CG-AA
• chr1-17044823-TCG-CAA

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_ModerateO3_ModerateO5_SupportingO6_SupportingO7_ModerateO8_Supporting

The NM_003000.3(SDHB):c.137G>T (p.Arg46Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene SDHB is a tumor suppressor gene (CancerMine: 12 TSG, 1 driver citations). The gene SDHB is a cancer driver gene (CancerMine: 12 TSG, 1 driver citations). The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,461,790 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. 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: "SCV000554015: Experimental studies have shown that this missense change affects SDHB function (PMID:23175444)." 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.R46G: Pathogenic (ClinVar VariationId 12785, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R46?: Uncertain_significance (ClinVar VariationId 591278, 0 stars); p.R46P: Uncertain_significance (ClinVar VariationId 3756934, 1 star); p.R46= (synonymous): Likely_benign (ClinVar VariationId 1100244, 1 star); p.R46= (synonymous): Benign/Likely_benign (ClinVar VariationId 646758, 2 stars); p.R46= (synonymous): Likely_benign (ClinVar VariationId 937404, 1 star) The variant has been observed in cBioPortal in 2 samples across 2 studies and 2 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.14
• Publications: 62 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (2.0 pts): ClinVar germline P/LP in TSG (★★)
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000000, AC = 2 — absent/extremely rare (O3 moderate [+2])
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Moderate: ≥10 same AA change, or strong functional domain signal; No cancerhotspots.org hit at this position; UniProt domain: 121 pathogenic, 13 benign (OR vs. background: 45.0).; ±8 AA neighbourhood: 5 pathogenic, 2 benign (OR vs. background: 11.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 0.44 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

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.137G>T p.Arg46Leu	missense	Exon 2 of 8	Prot: NP_002991.2 UniProt:
	SDHB NM_001407361.1		c.137G>T p.Arg46Leu	missense	Exon 2 of 8	Prot: NP_001394290.1 UniProt:

SDHB NM_003000.3

MANE Select

HGVSc / HGVSpc.137G>Tp.Arg46Leu

Exon rankExon 2 of 8

missense

Prot: NP_002991.2UniProt: P21912

SDHB NM_001407361.1

HGVSc / HGVSpc.137G>Tp.Arg46Leu

Exon rankExon 2 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.137G>T p.Arg46Leu	missense	Exon 2 of 8	Prot: ENSP00000364649.3 UniProt:
	SDHB ENST00000714034.1		c.182G>T p.Arg61Leu	missense	Exon 3 of 9	Prot: ENSP00000519325.1 UniProt:
	SDHB ENST00000925621.1		c.137G>T p.Arg46Leu	missense	Exon 2 of 8	Prot: ENSP00000595680.1 UniProt:

SDHB ENST00000375499.8

TSL:1MANE Select

HGVSc / HGVSpc.137G>Tp.Arg46Leu

Exon rankExon 2 of 8

missense

Prot: ENSP00000364649.3UniProt: P21912

SDHB ENST00000714034.1

HGVSc / HGVSpc.182G>Tp.Arg61Leu

Exon rankExon 3 of 9

missense

Prot: ENSP00000519325.1UniProt: A0AAQ5BHC9

SDHB ENST00000925621.1

HGVSc / HGVSpc.137G>Tp.Arg46Leu

Exon rankExon 2 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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 0.00000137	AC:2	Hom:0	AN:1461790	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)
1	-	-	Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 (1)
1	-	-	Pheochromocytoma/paraganglioma syndrome 4 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	31
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-8.8
GPN-Star score	N/A	8.8
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.95	D
Mutation Taster	N/A	10/90	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.6	H
PhyloP100	Uncertain	7.1
popEVE	Benign	-3.8
PrimateAI	Uncertain	0.63	T
PromoterAI	N/A	-0.051	Neutral
PROVEAN	Pathogenic	-5.5	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.96
VESM-3B	Benign	-13

Showing 31 of 31 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: rs772551056;

hg19: chr1-17371319;

COSMIC: COSV64965552;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar