NM_003000.3:c.423+20T>A

Variant names:

• chr1-17028580-A-T
• rs190139590
• NM_003000.3:c.423+20T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003000.3(SDHB):​c.423+20T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,613,868 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (29 hom.)
• Consequence: SDHB NM_003000.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:15
• Conservation: PhyloP100: -0.0320
• Publications: 5 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-17028580-A-T is Benign according to our data. Variant chr1-17028580-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36769.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00192 (292/152330) while in subpopulation SAS AF = 0.00745 (36/4830). AF 95% confidence interval is 0.00553. There are 1 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3	c.423+20T>A		intron_variant	Intron 4 of 7	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.369+74T>A		intron_variant	Intron 4 of 7		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.423+20T>A		intron_variant	Intron 4 of 7	1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 292 AN: 152212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00314 AC: 789 AN: 251332 AF XY: 0.00361

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00332 AC: 4852 AN: 1461538 Hom.: 29 Cov.: 32 AF XY: 0.00358 AC XY: 2604 AN XY: 727118

African (AFR) AF: 0.000359 AC: 12 AN: 33468

American (AMR) AF: 0.00203 AC: 91 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00620 AC: 162 AN: 26136

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

South Asian (SAS) AF: 0.0100 AC: 864 AN: 86246

European-Finnish (FIN) AF: 0.000507 AC: 27 AN: 53288

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.00309 AC: 3433 AN: 1111824

Other (OTH) AF: 0.00376 AC: 227 AN: 60388

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.00196 AC XY: 146 AN XY: 74500

African (AFR) AF: 0.000385 AC: 16 AN: 41570

American (AMR) AF: 0.00242 AC: 37 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00253 AC: 172 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00237 Hom.: 0

Bravo AF: 0.00191

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Jul 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SDHB: BS2 -

Jul 07, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SDHB c.423+20T>A variant was identified in the in heterozygous state in the tumour of one patient with pheochromocytoma (Pantaleo_2014_23612575) and in the tumours of two patients with Carney Triad (association of paragangliomas, pulmonary chondromas, and gastrointestinal stromal tumors with variety of other lesions including pheochromocytomas and adrenocortical tumors) who were also found to have SDHD c.388insG variants (Szarek_2015_25808178). The variant was also identified in dbSNP (ID: rs190139590) as “With Likely pathogenic allele”. The variant was found in ClinVar with conflicting interpretations of pathogenicity as it was classified as likely benign by Children's Mercy Hospital and Clinics, GeneDx, and Laboratory for Molecular Medicine at Partners HealthCare Personalized Medicine, benign by Prevention Genetics and Invitae, but was classified as likely pathogenic by Integrated Genetics/Laboratory Corporation of America. The variant was found in LOVD 3.0 where it was reported as likely benign. The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 847 of 282734 chromosomes (8 homozygous) at a frequency of 0.002996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 295 of 30614 chromosomes (freq: 0.009636), Ashkenazi Jewish in 69 of 10370 chromosomes (freq: 0.006654), Other in 28 of 7224 chromosomes (freq: 0.003876), European (Non-Finnish) in 370 of 129148 chromosomes (freq: 0.002865), Latino in 71 of 35438 chromosomes (freq: 0.002003), European (Finnish) in 10 of 25020 chromosomes (freq: 0.0004), African in 3 of 24966 chromosomes (freq: 0.00012) and East African in 1 of 19954 chromosomes (freq: 0.00005). Pathogenic variants in SDHB have been associated with Cowden Syndrome, an autosomal dominant condition with an estimated prevalence of 1 in 200 000 and Paragangliomas, an autosomal dominant condition with an estimated prevalence of 1 in 1 000 000. The observed allele frequency is therefore higher than would be expected for the disorder. Three in silico splicing programs (SpliceSiteFinder-like, MaxEntScan, NNSPLICE) predict a greater than 10% change in splicing which would lead to the creation of a new 3' splice site, however MutationTaster predicts that this variant is a polymorphism. This information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Pantaleo, Maria A., et al. "Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST." European Journal of Human Genetics 22.1 (2014): 32. Szarek, Eva, et al. "Carney triad, SDH-deficient tumors, and Sdhb+/− mice share abnormal mitochondria." Endocrine-related cancer 22.3 (2015): 345-352. -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:5

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been classified in HGMD as DM. It has been seen in 2 patients with pheochromocytomas and one with GIST. It is present with a MaxMAF of 0.89% in ExAC (high for disease frequency - 0.8/100,000 person-years). It is classified in ClinVar with 1 star as benign/likely benign by Invitae, GeneDx, Prevention genetics and as likely path by LabCorp (in 2011). -

Jun 22, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SDHB c.423+20T>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and 4/5 splice prediction tools predict changes of a cryptic splicing site. ESEfinder predicts changes of RNA splicing enhancer sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 374/121320 control chromosomes (4 homozygotes) at a frequency of 0.0030828, which is approximately 3523 times the estimated maximal expected allele frequency of a pathogenic SDHB variant (0.0000009), suggesting this variant is likely a benign polymorphism. This variant has been reported in the affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Aug 06, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.423+20T>A intronic variant results from a T to A substitution 20 nucleotides after coding exon 4 in the SDHB gene. In one study, this alteration was reported in 2 apparently unrelated individuals with an adrenal pheochromocytoma diagnosed prior to age 50 (Srirangalingam U et al. Clin Endocrinol. 2008 Oct;69(4):587-96). Neither of these probands had an identifiable VHL mutation; however, other susceptibility genes were not assessed. Authors classified c.423+20T>A as a mutation, but cautioned that further studies were needed to confirm pathogenicity. This variant was previously reported in the SNPDatabase as rs190139590. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.22% (28/13006), having been observed in 0.02% (1/4406) of African American alleles, and in 0.31% (27/8600) of European American alleles studied. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 0.05% (1/2184). The highest observed frequency was 1 of 178 (0.56%) British chromosomes studied. To date, this alteration has been detected with an allele frequency of approximately 0.03% (greater than 6100 alleles tested) in our clinical cohort. Based on nucleotide sequence alignment, this position is poorly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a cryptic splice acceptor site in close proximity to the native donor site; however, direct evidence is unavailable. Since supporting evidence for this variant is conflicting at this time, the clinical significance of c.423+20T>A remains unclear. -

May 29, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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Pheochromocytoma/paraganglioma syndrome 4 Uncertain:1

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastrointestinal stromal tumor Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		-0.032
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs190139590; hg19: chr1-17355075; COSMIC: COSV105926644;