1-17022685-G-C

Variant names:

• chr1-17022685-G-C
• rs138996609
• NM_003000.3:c.688C>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_003000.3(SDHB):​c.688C>G​(p.Arg230Gly) variant causes a missense change. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R230C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.98
• Publications: 1 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 12 ACMG points.

• PM1: In a turn (size 4) in uniprot entity SDHB_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr1-17022685-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 185077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 1-17022685-G-C is Pathogenic according to our data. Variant chr1-17022685-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1755980.Status of the report is criteria_provided_single_submitter, 1 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.688C>G	p.Arg230Gly	missense	Exon 7 of 8	NP_002991.2
	SDHB	NM_001407361.1		c.634C>G	p.Arg212Gly	missense	Exon 7 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.688C>G	p.Arg230Gly	missense	Exon 7 of 8	ENSP00000364649.3
	SDHB	ENST00000714034.1		c.733C>G	p.Arg245Gly	missense	Exon 8 of 9	ENSP00000519325.1
	SDHB	ENST00000491274.6	TSL:5	c.646C>G	p.Arg216Gly	missense	Exon 7 of 8	ENSP00000480482.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 24, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R230G variant (also known as c.688C>G), located in coding exon 7 of the SDHB gene, results from a C to G substitution at nucleotide position 688. The arginine at codon 230 is replaced by glycine, an amino acid with dissimilar properties. In one study, this alteration was found in three individuals affected with paragangliomas and in 22 unaffected carriers out of a total of 45 screened individuals from two unrelated families (Castellano M, et al. Ann. N. Y. Acad. Sci. 2006;1073():156-65). Two different alterations located at the same position, p.R230H and p.R230C, have been reported in patients with pheochromocytomas and/or paragangliomas (Amar et al. J Clin Oncol. 2005 Dec1; 23(34):8812-8, Said-Al-Naief et al. Head Neck Pathol 2008 Dec; 2(4): 272-8, Ricketts CJ et al. J. Urol. 2012; 188:2063-71, Cascón A et al. J. Clin. Endocrinol. Metab. 2009; 94:1701-5, Burnichon N et al. J. Clin. Endocrinol. Metab. 2009; 94:2817-27; Dahia PL et al. PLoS Genet. 2005 Jul;1(1):72-80; Neumann HP et al. Cancer Res. 2009 Apr 15;69(8):3650-6; Sevilla MA et al. Otolaryngol Head Neck Surg. 2009 May;140(5):724-9; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27; Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.00% (greater than 6100 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		6.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.85		Loss of ubiquitination at K233 (P = 0.0992)
MVP		0.99
MPC		0.64
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.96
Mutation Taster		=13/87	disease causing

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: rs138996609; hg19: chr1-17349180;