1-17044824-C-T

Variant names:

• chr1-17044824-C-T
• rs772551056
• NM_003000.3:c.137G>A
• SDHB p.Arg46Gln

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.137G>A (p.Arg46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000167 (AC=27) in the gnomAD database across 1,613,850 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000121. 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: "SCV000212994: This mutation has been shown to increase protein degradation and to reduce mutant protein half-life in transfected cell lines (Saxena N et al. J. Natl. Cancer Inst. 2016 Jan;108" 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) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25
• Conservation: PhyloP100: 7.14
• Publications: 47 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); SCV000212994: This mutation has been shown to increase protein degradation and to reduce mutant protein half-life in transfected cell lines (Saxena N et al. J. Natl. Cancer Inst. 2016 Jan;108; Yang C et al. FASEB J, 2012 Nov;26:4506-16). In addition, in vitro analyses have shown significantly reduced mitochondrial SDHB expression and a reduction in SDHB enzymatic activity compared to wild type (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Functional analysis of R46Q demonstrated complete loss of SDHB-SDHAF3 interaction (Dwight T et al. BMC Cancer, 2017 Jul;17:497). Structural analysis showed that the R46Q alteration impaired iron incorporation and Complex II biogenesis (Maio N et al. Cell Metab, 2014 Mar;19:445-57).; SCV000235637: "Published functional studies demonstrate a damaging effect: reduced protein stability, decreased succinate dehydrogenase activity, and increased hypoxia-inducible factors (Giminez-Roqueplo et al., 2002; Yang et al., 2012; Saxena et al., 2015)"; SCV000886095: Further, functional analyses of p.Arg46Gln demonstrate decreased succinate dehydrogenase expression and activity and increased hypoxia-inducible factors (Saxena 2016).; SCV004045422: Functional studies indicate this variant impacts protein function [PMID: 22677546, 26719882, 25972245].; SCV004362282: "Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844)."; SCV004821943: "Functional studies have shown that this variant results in decreased mitochondrial expression, decreased succinate dehydrogenase activity, and reduced interaction with SDHA and SDHAF3 (PMID: 22835832, 23175444, 24606901, 25972245, 26719882, 28738844)."; SCV000287759: Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832, 25972245, 26719882).; SCV005358433: Functional in vitro assays show that this variant leads to protein instability (Yang et al. 2012. PubMed ID: 22835832; Saxena et al. 2016. PubMed ID: 26719882).
	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: 5 pathogenic, 2 benign (OR vs. background: 11.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000121 — 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.R46G: Pathogenic (ClinVar VariationId 12785, 2 stars); Other variants at the same amino acid residue (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)
	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 (25/25 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.137G>A p.Arg46Gln	missense	Exon 2 of 8	Prot: NP_002991.2 UniProt:
	SDHB NM_001407361.1		c.137G>A p.Arg46Gln	missense	Exon 2 of 8	Prot: NP_001394290.1 UniProt:

SDHB NM_003000.3

MANE Select

HGVSc / HGVSpc.137G>Ap.Arg46Gln

Exon rankExon 2 of 8

missense

Prot: NP_002991.2UniProt: P21912

SDHB NM_001407361.1

HGVSc / HGVSpc.137G>Ap.Arg46Gln

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>A p.Arg46Gln	missense	Exon 2 of 8	Prot: ENSP00000364649.3 UniProt:
	SDHB ENST00000714034.1		c.182G>A p.Arg61Gln	missense	Exon 3 of 9	Prot: ENSP00000519325.1 UniProt:
	SDHB ENST00000925621.1		c.137G>A p.Arg46Gln	missense	Exon 2 of 8	Prot: ENSP00000595680.1 UniProt:

SDHB ENST00000375499.8

TSL:1MANE Select

HGVSc / HGVSpc.137G>Ap.Arg46Gln

Exon rankExon 2 of 8

missense

Prot: ENSP00000364649.3UniProt: P21912

SDHB ENST00000714034.1

HGVSc / HGVSpc.182G>Ap.Arg61Gln

Exon rankExon 3 of 9

missense

Prot: ENSP00000519325.1UniProt: A0AAQ5BHC9

SDHB ENST00000925621.1

HGVSc / HGVSpc.137G>Ap.Arg46Gln

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000132	AC:2	Hom:0	AN:152060	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251358	Cov:
GnomAD4 exome	AF: 0.0000171	AC:25	Hom:0	AN:1461790	Cov:32
GnomAD4 genome	AF: 0.0000132	AC:2	Hom:0	AN:152060	Cov:32
TOPMed (Bravo)	AF: 0.0000151	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000126	AC:3	Hom:0	AN:238764	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000570	AC:7	Hom:0	AN:122586	Cov:
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
Epi25(Epilepsy)	0.0000238	1	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000392	3	76580	0.00000751	1	133232

Showing 3 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
6	-	-	Pheochromocytoma/paraganglioma syndrome 4 (6)
5	-	-	Hereditary pheochromocytoma and paraganglioma (5)
4	-	-	not provided (4)
2	-	-	SDHB-related disorder (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	-	-	Inherited phaeochromocytoma and paraganglioma excluding NF1 (1)
1	-	-	Inherited renal cancer (1)
1	-	-	Pheochromocytoma (1)
1	-	-	Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 (1)
1	-	-	Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1861848:Pheochromocytoma/paraganglioma syndrome 4 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.97
GPN-Star LLR	N/A	-7.1
GPN-Star score	N/A	7.1
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.95	D
Mutation Taster	N/A	6/94	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.6	H
PhyloP100	Uncertain	7.1
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.55	T
PromoterAI	N/A	-0.023	Neutral
PROVEAN	Uncertain	-3.3	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R	N/A	0.94
VESM-3B	Benign	-11

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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar