rs786202100

Variant names:

• chr1-17044790-ATGAGG-A
• rs786202100
• NM_003000.3:c.166_170delCCTCA

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.166_170delCCTCA​(p.Pro56TyrfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SDHB NM_003000.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.06
• Publications: 14 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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-17044790-ATGAGG-A is Pathogenic according to our data. Variant chr1-17044790-ATGAGG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 185342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3	c.166_170delCCTCA	p.Pro56TyrfsTer5	frameshift_variant	Exon 2 of 8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.166_170delCCTCA	p.Pro56TyrfsTer5	frameshift_variant	Exon 2 of 8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.166_170delCCTCA	p.Pro56TyrfsTer5	frameshift_variant	Exon 2 of 8	1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461830 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111968

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Pathogenic:2

Dec 07, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 15328326, 21934479, 25130709, 28152038] -

Jan 04, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SDHB c.166_170delCCTCA (p.Pro56TyrfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is also known as c.32_36delCCTCA in HGVS and 300-4delCCTCA in the literature. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251378 control chromosomes (gnomAD). c.166_170delCCTCA has been reported in the literature in multiple individuals affected with Paraganglioma and/or Pheochromocytoma (examples: Neumann_2004, Cascon_2009, Burnichon_2009, Andrews_2018 and Benn_2018). These data indicate that the variant is associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Feb 07, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Also known as Pro28TyrfsX5; This variant is associated with the following publications: (PMID: 17652212, 25130709, 28152038, 30050099, 31216007, 21934479, 15328326, 31431315, 31092265, 30262796, 18551016, 28973655, 20208144, 18382370, 31492822, 24436918, 28529006, 31589614, 19258401, 33900943, 34313605) -

May 21, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHB c.166_170del (p.Pro56Tyrfs*5) variant alters the translational reading frame of the SDHB mRNA and causes the premature termination of SDHB protein synthesis. This variant has been reported in the published literature in individuals and families affected with PGL-PCC syndrome (PMIDs: 15328326 (2004), 21934479 (2011), 31431315 (2019)) and pituitary adenoma (PMID: 34313605 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:2

Oct 29, 2019

Division of Medical Genetics, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the literature in multiple individuals affected with pheochromocytoma and/or paraganglioma [Neumann 2004, Mora 2006, Amar 2007, Cascon 2009, Gill 2011, Jove 2014]. This variant leads to a translational frameshift and the introduction of a premature termination codon 5 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of SDHB is a well-established mechanism of disease for hereditary paraganglioma-pheochromocytoma syndrome [Burnichon 2009, Ricketts 2010]. This variant is not present in population databases (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PM2; PVS1 -

Mar 22, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not specified Pathogenic:1

Mar 21, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHB c.166_170delCCTCA; p.Pro56fs variant (rs786202100), also published as 300_304delCCTCA, is reported in the literature in numerous individuals affected with paraganglioma and/or pheochromocytoma (Amar 2007, Burnichon 2009, Cascon 2009, Gill 2011, Jove 2014, Mora 2006, Neumann 2004). This variant has been discussed as a founder mutation in affected individuals of Spanish descent (Cascon 2009). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by several laboratories in ClinVar (Variation ID: 185342). This variant causes a frameshift by deleting five nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Amar L et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007 Oct;92(10):3822-8. Burnichon N et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27. Cascon A et al. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab. 2009 May;94(5):1701-5. Gill AJ et al. Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol. 2011 Oct;35(10):1578-85. Jove et al. Simultaneous KIT mutation and succinate dehydrogenase (SDH) deficiency in a patient with a gastrointestinal stromal tumour and Carney-Stratakis syndrome: a case report. Histopathology. 2014 Nov;65(5):712-7. Mora J et al. Pediatric paraganglioma: an early manifestation of an adult disease secondary to germline mutations. Pediatr Blood Cancer. 2006 Nov;47(6):785-9. Neumann HP et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1847319:Carney-Stratakis syndrome;C1861848:Pheochromocytoma/paraganglioma syndrome 4;C5543176:Mitochondrial complex 2 deficiency, nuclear type 4 Pathogenic:1

Apr 10, 2022

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

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Pro56Tyrfs*5) in the SDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with pheochromocytoma and/or paraganglioma (PMID: 15328326, 16304664, 17652212, 19258401, 21934479, 25130709). This variant is also known as 300-4delCCTCA or c.300_304delCCTCA. ClinVar contains an entry for this variant (Variation ID: 185342). For these reasons, this variant has been classified as Pathogenic. -

Gastrointestinal stromal tumor Pathogenic:1

Feb 18, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 26, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.166_170delCCTCA pathogenic mutation, located in coding exon 2 of the SDHB gene, results from a deletion of 5 nucleotides at nucleotide positions 166 to 170, causing a translational frameshift with a predicted alternate stop codon (p.P56Yfs*5). This well-described mutation has been identified in numerous individuals with various tumors across the SDHx spectrum, including pheochromocytoma, paraganglioma, gastrointestinal stromal tumor (GIST), and/or renal cell carcinoma (Neumann HP et al. JAMA 2004 Aug;292(8):943-51; Mora J et al. Pediatr. Blood Cancer 2006 Nov;47(6):785-9; Amar L et al. J. Clin. Endocrinol. Metab. 2007 Oct;92(10):3822-8; Persu A et al. J. Hypertens. 2008 Jul;26(7):1395-401; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Gill AJ et al. Am. J. Surg. Pathol. 2011 Oct;35(10):1578-85). Haplotype analysis suggests that the c.166_170delCCTCA alteration is enriched in the Spanish population due to a founder effect (Cascón A et al. J. Clin. Endocrinol. Metab. 2009 May;94(5):1701-5). This alteration was originally described as c.300-4delCCTCA in the literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

SDHB-related disorder Pathogenic:1

Mar 09, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also referred to as 300-4delCCTCA or c.300_304delCCTCA in the literature. This frameshifting variant in exon 2 of 8 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). Loss-of-function variation in SDHB is an established mechanism of disease (PMID: 20301715, 19454582, 19802898). This variant has been previously reported as a heterozygous change in patients with hereditary paraganglioma-pheochromocytoma syndromes (PMID: 31431315, 31492822, 15328326, 16304664, 17652212, 19258401, 21934479, 25130709, 30262796, 28152038, 30050099). The c.166_170del (p.Pro56TyrfsTer5) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.166_170del (p.Pro56TyrfsTer5) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs786202100; hg19: chr1-17371285;