NM_003000.3:c.137G>A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_003000.3(SDHB):​c.137G>A​(p.Arg46Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,613,850 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 (★★). 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; 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).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46L) has been classified as Likely pathogenic.

• 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:21
• Conservation: PhyloP100: 7.14
• Publications: 60 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: Genomics England PanelApp, G2P, Orphanet
• gastrointestinal stromal tumor

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

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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: 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).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 34 uncertain in NM_003000.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-17044824-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 412478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-17044824-C-T is Pathogenic according to our data. Variant chr1-17044824-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003000.3. You can select a different transcript below to see updated ACMG 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	NP_002991.2	P21912
	SDHB	NM_001407361.1		c.137G>A	p.Arg46Gln	missense	Exon 2 of 8	NP_001394290.1	A0AAQ5BHD9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	ENST00000375499.8	TSL:1 MANE Select	c.137G>A	p.Arg46Gln	missense	Exon 2 of 8	ENSP00000364649.3	P21912
	SDHB	ENST00000714034.1		c.182G>A	p.Arg61Gln	missense	Exon 3 of 9	ENSP00000519325.1	A0AAQ5BHC9
	SDHB	ENST00000925621.1		c.137G>A	p.Arg46Gln	missense	Exon 2 of 8	ENSP00000595680.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251358 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461790 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727202

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111954

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74250

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000127 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hereditary pheochromocytoma and paraganglioma (4)
4	-	-	not provided (4)
4	-	-	Pheochromocytoma/paraganglioma syndrome 4 (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	-	-	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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		7.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.94		Loss of MoRF binding (P = 0.0347)
MVP		0.99
MPC		0.75
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.92
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs772551056; hg19: chr1-17371319;