rs587782703

Variant names:

• chr1-17053947-C-A
• rs587782703
• NM_003000.3:c.72+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-17053947-C-A
• chr1-17053947-C-G
• chr1-17053947-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003000.3(SDHB):​c.72+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000158 in 1,459,768 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SDHB NM_003000.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 3.92
• Publications: 20 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 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PP5: Variant 1-17053947-C-A is Pathogenic according to our data. Variant chr1-17053947-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 142764.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.72+1G>T		splice_donor_variant, intron_variant	Intron 1 of 7	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.72+1G>T		splice_donor_variant, intron_variant	Intron 1 of 7		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.72+1G>T		splice_donor_variant, intron_variant	Intron 1 of 7	1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000124 AC: 3 AN: 242838 AF XY: 0.0000151

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: 0.0000276

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1459768 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726122

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1110878

Other (OTH) AF: 0.00 AC: 0 AN: 60266

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000499 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:5

Aug 27, 2021

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.72+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5` splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and indicated that the first part of intron 1 was transcribed with the frameshift resulting in a stop codon in the middle of exon 2, predicting a truncated protein (Pasini_2007). The variant allele was found at a frequency of 1.2e-05 in 242838 control chromosomes (gnomAD). c.72+1G>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (Pasini_2007, Benn_2018, Richter_2019, Dwight_2021). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

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Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 10, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHB c.72+1G>T intronic change results in a G to T substitution at the +1 position of intron 1 of the SDHB gene. This variant is predicted to result in loss of the native splice donor site and abnormal gene splicing, resulting in nonsense-mediated decay or an abnormal protein product (PVS1). This variant has a maximum subpopulation frequency of 0.0028% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/1-17380442-C-A?dataset=gnomad_r2_1). This variant has been reported in individuals with pheochromocytoma (PMID: 16317055, 18419787, 23666964, 31492822), paraganglioma (PMID: 16472267, 16912137, 20418362, 29909963, 30050099), gastrointestinal stromal tumor (PMID: 17804857), and renal cell carcinoma (PMID: 20459544, 26556299). This variant is also known as IVS1+1G>T in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_Supporting. -

Aug 23, 2024

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 to T nucleotide substitution at the +1 position of intron 1 of the SDHB gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional RNA assay has shown that the variant results in aberrant mRNA resulting from the retention of intron 1 (PMID: 17667967). This variant has been reported in numerous individuals affected with paraganglioma and pheochromocytoma (PMID:16317055, 16472267, 16912137, 17667967, 17804857, 18419787, 20418362, 20459544, 23512077, 23666964, 26556299, 28374168, 29909963, 30050099, 30201732, 31492822, 33300499, 33362715). This variant has been identified in 3/242838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHB function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Dec 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to T nucleotide substitution at the +1 position of intron 1 of the SDHB gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional RNA assay has shown that the variant results in aberrant mRNA resulting from the retention of intron 1 (PMID: 17667967). This variant has been reported in numerous individuals affected with paraganglioma and pheochromocytoma (PMID:16317055, 16472267, 16912137, 17667967, 17804857, 18419787, 20418362, 20459544, 23512077, 23666964, 26556299, 28374168, 29909963, 30050099, 30201732, 31492822, 33300499, 33362715). This variant has been identified in 3/242838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHB function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:3

Aug 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site 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 at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26916530, 19215943, 21934479, 16912137, 16472267, 19864450, 29204718, 23666964, 25741136, 20418362, 20459544, 18419787, 17200167, 24623741, 16317055, 17667967, 19522823, 28973655, 28374168, 27910947, 26556299, 29909963, 30694796, 29623478, 28748451, 30050099, 31492822, 32581362, 29386252, 33087929, 32741965, 30787465) -

Aug 22, 2014

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHB c.72+1G>T variant (also known IVS1+1G>T) disrupts a canonical splice-donor site and interferes with normal SDHB mRNA splicing. The frequency of this variant in the general population, 0.000028 (3/108524 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, this variant has been shown to cause aberrant splicing in patient RNA (PMID: 17667967 (2008)), and reported in multiple individuals with PGL-PCC (PMIDs: 33362715 (2020), 31492822 (2020), 30201732 (2018), 16912137 (2006), 16317055 (2006)), gastrointestinal stromal tumor (PMIDs: 17667967 (2008), 17804857 (2007)), and renal cell carcinoma (PMIDs: 35441217 (2022), 26556299 (2016), 20459544 (2010)). Based on the available information, this variant is classified as pathogenic. -

Dec 10, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 16, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.72+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the SDHB gene. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHB-related disease (Ambry internal data; Benn DE et al. J Clin Endocrinol Metab. 2006: 91(3); 827-836; Brouwers FM et al. J Endocrinol Metab. 2006;91(11):4505-9; Timmers HJ et al. J Clin Endocrinol Metab. 2007;92(3): 779-86; Tsang VH et al. Endocr Relat Cancer. 2014 May 6;21(3):415-26; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143(8):1421-1435; Pasini B et al. Eur J Hum Genet 2008 Jan;16(1):79-88; McWhinney SR et al. N Engl J Med 2007 Sep;357(10):1054-6; Rattenberry E et al. J Clin Endocrinol Metab 2013 Jul;98(7):E1248-56; Elston MS et al. Intern Med J 2006 Feb;36(2):129-31). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic. -

Jan 26, 2018

Academic Department of Medical Genetics, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -

not specified Pathogenic:1

Jun 10, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHB c.72+1G>T variant (rs587782703) is reported in the literature in individuals affected with pheochromocytoma (Benn 2006, Timmers 2007, Tsang 2014), paraganglioma (Brouwers 2006), gastrointestinal tumor (Pasini 2008, McWhinney 2008), and renal cell carcinoma (Schrader 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 142764), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 1, which is likely to negatively impact gene function, and functional analyses of patient mRNA shows aberrant splicing (Pasini 2008). Additionally, other variants at this nucleotide (c.72+1G>A, c.72+1G>C) have been reported in individuals with pheochromocytoma or paraganglioma and are considered pathogenic (Burnichon 2009, Ricketts 2010). Based on available information, the c.72+1G>T variant is considered to be pathogenic. References: Benn DE et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36. Brouwers FM et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006 Nov;91(11):4505-9. 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. McWhinney SR et al. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med. 2007 Sep 6;357(10):1054-6. Pasini B et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008 Jan;16(1):79-88. Ricketts CJ et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 2010 Jan;31(1):41-51. Schrader KA et al. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncol. 2016 Jan;2(1):104-11. Timmers HJ et al. Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. J Clin Endocrinol Metab. 2007 Mar;92(3):779-86. Tsang VH et al. Overexpression of miR-210 is associated with SDH-related pheochromocytomas, paragangliomas, and gastrointestinal stromal tumours. Endocr Relat Cancer. 2014 May 6;21(3):415-26. -

Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:1

Jan 30, 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: 23512077, 33362715, 30201732, 28374168]. -

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

Jan 07, 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 1 of the SDHB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with clinical features of SDHB-related conditions (PMID: 16317055, 16472267, 16912137, 17667967, 18419787, 20418362, 20459544, 23666964). This variant is also known as IVS1+1G>T. ClinVar contains an entry for this variant (Variation ID: 142764). Studies have shown that disruption of this splice site results in retention of part of intron 1, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 17667967; internal data). For these reasons, this variant has been classified as Pathogenic. -

Gastrointestinal stromal tumor Pathogenic:1

Sep 27, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SDHB-related disorder Pathogenic:1

Jun 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SDHB c.72+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in multiple individuals with pheochromocytoma, paraganglioma, gastrointestinal stromal tumors, and renal cell carcinoma (Benn et al. 2006. PubMed ID: 16317055; Srirangalingam et al. 2008. PubMed ID: 18419787; Pasini et al. 2007. PubMed ID: 17667967; McWhinney et al. 2007. PubMed ID: 17804857; Housley et al. 2010. PubMed ID: 20459544; Schrader et al. 2016. PubMed ID: 26556299 ). This variant is reported in 0.0028% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142764/). Variants that disrupt the consensus splice donor site in SDHB are expected to be pathogenic. This variant is interpreted as pathogenic. -

Carney-Stratakis syndrome Pathogenic:1

Jan 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Benign	0.70	D
PhyloP100		3.9
GERP RS		5.1
PromoterAI		-0.41	Neutral
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		4.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 2
DS_DL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs587782703; hg19: chr1-17380442;