1-17028599-C-T

Variant names:

• chr1-17028599-C-T
• rs398122805
• NM_003000.3:c.423+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003000.3(SDHB):​c.423+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SDHB NM_003000.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 7.23
• Publications: 37 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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.7, offset of -25, new splice context is: catGTatgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-17028599-C-T is Pathogenic according to our data. Variant chr1-17028599-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 29896.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.423+1G>A		splice_donor intron	N/A	NP_002991.2
	SDHB	NM_001407361.1		c.369+55G>A		intron	N/A	NP_001394290.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	ENST00000375499.8	TSL:1 MANE Select	c.423+1G>A		splice_donor intron	N/A	ENSP00000364649.3
	SDHB	ENST00000714034.1		c.468+1G>A		splice_donor intron	N/A	ENSP00000519325.1
	SDHB	ENST00000491274.6	TSL:5	c.381+1G>A		splice_donor intron	N/A	ENSP00000480482.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251374 AF XY: 0.0000147

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: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727198

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

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

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111954

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Dec 19, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHB c.423+1G>A variant (rs398122805) is described in the medical literature in individuals and families with paraganglioma and pheochromocytoma (Bayley 2006, Ercolino 2009, Erlic 2009, Hensen 2012, Hes 2010). The variant has also been shown to have reduced penetrance (Hes 2010). The variant is described in the ClinVar database (Variation ID: 29896) and in the Genome Aggregation Database in 3 out of 251,374 alleles. This variant occurs in the conserved splicing signal and has been shown to result in an in-frame deletion of 18 amino acids (Ercolino 2009). Considering available information, this variant is classified as pathogenic. References: Bayley JP et al. Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma. BMC Med Genet. 2006 7:1. Ercolino T et al. Malignant extra-adrenal pheochromocytoma caused by an SDHB intronic variation leading to a 54-bp deletion in exon 4. J Endocrinol Invest. 2009 32(2):111-4. Erlic Z et al. Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients. Clin Cancer Res. 2009 15(20):6378-85. Hensen EF et al. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin Genet. 2012 Mar;81(3):284-8. Hes FJ et al. Low penetrance of a SDHB mutation in a large Dutch paraganglioma family. BMC Med Genet. 2010 11:92.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 07, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22948026, 21934479, 26283294, 19454582, 30658386, 19215943, 20540712, 19825962, 25494863, 23666964, 24886695, 25047027, 19411806, 21348866, 16317055, 14715873, 19258401, 25371406, 26269449, 14595761, 22009375, 27910947, 25025441, 26259135, 28503760, 28374168, 28490599, 29951630, 30549360, 30050099, 30273935, 29794110, 28748451, 16405730, 29625052, 30787465, 27737332, 34308104, 34436013, 34703596, 31492822, 32741965)

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 08, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP4, PM2_moderate, PM6, PS4_moderate, PVS1_strong

Hereditary pheochromocytoma-paraganglioma Pathogenic:3

Aug 18, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G>A nucleotide substitution at the +1 position of intron 4 of the SDHB gene. Experimental RNA studies have shown that this variant causes an in-frame deletion of 54 nucleotides in exon 4 resulting in deletion of 18 amino acids in the 4Fe-4S ferredoxin-type domain (PMID: 19411806). This variant has been reported in at least ten individuals affected with hereditary paranganglioma-pheochromocytoma syndrome (PMID: 16405730, 19411806, 19825962, 20540712, 21348866, 21934479, 25047027, 26283294, 28503760, 30050099, 31492822). This variant has been identified in 3/251374 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHB function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:2

Mar 13, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 28070496, 27011036, 26259135].

Mar 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1861848:Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 of the SDHB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is present in population databases (rs398122805, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with paraganglioma (PGL) and/or pheochromocytoma (PCC) (PMID: 16405730, 19411806, 19825962, 20540712, 21348866, 25047027). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29896). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (internal data). This variant disrupts the p.Asp138 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22517554, 31492822, 31666924). 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.

Gastrointestinal stromal tumor Pathogenic:1

Nov 26, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 28, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.423+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the SDHB gene. This mutation is a known Dutch founder mutation, and it has been reported in numerous Dutch families with hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndrome (Hensen EF et al. Clin Genet, 2012 Mar;81:284-8; Rijken JA et al. Clin Genet, 2018 Jan;93:60-66). In addition, this mutation has been reported in other individuals with PGL-PCC in the literature (Erlic Z et al. Clin Cancer Res, 2009 Oct;15:6378-85; Gill AJ et al. Am. J. Surg. Pathol., 2011 Oct;35:1578-85). It was also identified as a de novo occurrence in a 6-year-old patient with an abdominal paraganglioma (Imamura H et al. Eur. J. Pediatr., 2016 Jan;175:137-41). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration abolishes the native donor site and activates a cryptic donor site in the adjacent exon (Bayley JP et al. BMC Med Genet, 2006 Jan;7:1; Ercolino T et al. J. Endocrinol. Invest., 2009 Feb;32:111-4; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.2
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398122805; hg19: chr1-17355094; COSMIC: COSV64965540; COSMIC: COSV64965540;