NM_003000.3:c.136C>G

Variant names:

• chr1-17044825-G-C
• rs74315370
• NM_003000.3:c.136C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003000.3(SDHB):​c.136C>G​(p.Arg46Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). 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: not found (cov: 32)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.56
• Publications: 55 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: Genomics England PanelApp, Ambry Genetics, 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 18 ACMG points.

• 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
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.987
• PP5: Variant 1-17044825-G-C is Pathogenic according to our data. Variant chr1-17044825-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 12785.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	NM_003000.3	MANE Select	c.136C>G	p.Arg46Gly	missense	Exon 2 of 8	NP_002991.2
	SDHB	NM_001407361.1		c.136C>G	p.Arg46Gly	missense	Exon 2 of 8	NP_001394290.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	ENST00000375499.8	TSL:1 MANE Select	c.136C>G	p.Arg46Gly	missense	Exon 2 of 8	ENSP00000364649.3
	SDHB	ENST00000463045.3	TSL:3	c.-36C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	ENSP00000481376.2
	SDHB	ENST00000714031.1		c.-36C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	ENSP00000519321.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:1

May 09, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:1

Aug 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 46 of the SDHB protein (p.Arg46Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma-pheochromocytoma syndrome (PMID: 14500403, 15328326, 19454582; Invitae). This variant is also known as 270C>G. ClinVar contains an entry for this variant (Variation ID: 12785). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 25972245, 28738844). This variant disrupts the p.Arg46 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 23175444). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 27, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R46G pathogenic mutation (also known as c.136C>G or c.270C>G), located in coding exon 2 of the SDHB gene, results from a C to G substitution at nucleotide position 136. The arginine at codon 46 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in several unrelated individuals diagnosed with paragangliomas and/or pheochromocytomas (Neumann HP et al. N Engl J Med. 2002 May 9;346(19):1459-66; Gimenez-Rogueplo AP et al. Cancer Res. 2003 Sep 1;63(17):5615-21; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27). Two other alterations at the same codon, p.R46Q and p.R46L, have also been reported as germline mutations in affected individuals (Panizza E et al. Hum Mol Genet. 2013 Feb 15;22(4):804-15; Miettinen M et al. Am J Surg Pathol. 2013 Feb;37(2):234-40; Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). The p.R46G substitution was associated with reduced SDH activity, and impairments in location of the enzyme to mitochondria and interaction with the SDHA subunit (Kim E et al, Endocr. Relat. Cancer 2015 Jun;22(3):387-97). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as a pathogenic mutation.

SDHB-related disorder Pathogenic:1

Mar 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SDHB c.136C>G variant is predicted to result in the amino acid substitution p.Arg46Gly. This variant has been reported in multiple individuals with a history of pheochromocytoma or paraganglioma (Neumann et al. 2002. PubMed ID: 12000816; Gimenez-Roqueplo et al. 2003. PubMed ID: 14500403; Burnichon et al. 2009. PubMed ID: 19454582; Garrett et al. 2022. PubMed ID: 34906457). In vitro functional studies have demonstrated that this variant leads to reduced mitochondrial expression and a loss of enzymatic activity (Kim et al. 2015. PubMed ID: 25972245). This variant has not been reported in a large population database and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12785/). Of note, additional missense variants at the same amino acid position (p.Arg46Gln, p.Arg46Leu) have also been shown to be functionally deleterious and reported as disease-causing in affected patients (Benn et al. 2003. PubMed ID: 12618761; Panizza et al. 2013. PubMed ID: 23175444; Kim et al. 2015. PubMed ID: 25972245; Garrett et al. 2022. PubMed ID: 34906457). Taken together, the p.Arg46Gly variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		1.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.93		Loss of MoRF binding (P = 0.0381)
MVP		0.99
MPC		0.79
ClinPred		1.0	D
GERP RS		2.4
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.96
Mutation Taster		=14/86	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: rs74315370; hg19: chr1-17371320;