NM_003000.3:c.590C>G

Variant names:

• chr1-17024025-G-C
• rs74315367
• NM_003000.3:c.590C>G

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.590C>G​(p.Pro197Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000273721: Authors of one study showed that the p.P197R alteration led to mitochondrial expression levels and SDH enzyme activity levels similar to that of wild type cells in vitro" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P197S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.96
• Publications: 18 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: SCV000273721: Authors of one study showed that the p.P197R alteration led to mitochondrial expression levels and SDH enzyme activity levels similar to that of wild type cells in vitro; however structural modeling predicted this alteration would affect the function of the electron path in the electron transport chain (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Based on internal structural analysis, P197R introduces a large, positively-charged side-chain into a functionally critical region of SDHB, and is likely to disrupt both ubiquinone binding and reduction of ubiquinone (Sun F et al. Cell. 2005 Jul;121:1043-57; Yankovskaya V et al. Science. 2003 Jan;299:700-4; Guo J et al. J. Biol. Chem. 2003 Nov;278:47629-35).; SCV000553988: Experimental studies have shown that this missense change does not substantially affect SDHB function (PMID: 18519664, 25972245, 28738844).
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 uncertain in NM_003000.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-17024026-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 845283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 1-17024025-G-C is Pathogenic according to our data. Variant chr1-17024025-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12779.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.590C>G	p.Pro197Arg	missense	Exon 6 of 8	NP_002991.2	P21912
	SDHB	NM_001407361.1		c.536C>G	p.Pro179Arg	missense	Exon 6 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.590C>G	p.Pro197Arg	missense	Exon 6 of 8	ENSP00000364649.3	P21912
	SDHB	ENST00000714034.1		c.635C>G	p.Pro212Arg	missense	Exon 7 of 9	ENSP00000519325.1	A0AAQ5BHC9
	SDHB	ENST00000925621.1		c.584C>G	p.Pro195Arg	missense	Exon 6 of 8	ENSP00000595680.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251186 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: 0.00000821 AC: 12 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Pheochromocytoma/paraganglioma syndrome 4 (3)
2	-	-	Hereditary pheochromocytoma and paraganglioma (2)
2	-	-	not provided (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		9.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.96		Gain of catalytic residue at P197 (P = 0.0672)
MVP		1.0
MPC		0.71
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.96
Mutation Taster		=1/99	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: rs74315367; hg19: chr1-17350520;