About SDHB
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SDHB c.-8G>C, p.?
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen SDHB VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_003000.3:c.-8G>C is extremely rare in population databases: gnomAD v2.1 allele frequency is 0.0011% (3/271,616 alleles), v4.1 allele frequency is 0.0012% (19/1,606,996 alleles), and it is absent from gnomAD-Canada. No homozygotes have been observed. The frequency is well below the 0.1% PM2 threshold, and grpmax FAF is 3.07e-06 (v2.1) and 8.06e-06 (v4.1).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen Endocrine Tumor Predisposition Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SDHB Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
19 / 1,606,996 alleles
gnomAD v4.1: 19 / 1,606,996 alleles. Recorded AF 1.18233e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.1045e-05; MAF= 0.00110%, 3/271616 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.42884e-05; MAF= 0.00243%, 3/123516 alleles, homozygotes = 0); grpmax FAF= 3.07e-06.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions
2 Uncertain significance · 1 Likely benign.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen SDHB VCEP v1.0.0, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 17 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_003000.3:c.-8G>C is a 5' UTR substitution located 8 bp upstream of the ATG start codon in SDHB.
The variant is extremely rare in population databases, with an allele frequency of 0.0011% in gnomAD v2.1 (3/271,616 alleles) and 0.0012% in gnomAD v4.1 (19/1,606,996 alleles), meeting PM2 at supporting strength.
No functional studies, case-control data, segregation data, de novo observations, or computational evidence are available to support any additional pathogenic or benign criteria.
The variant is present in ClinVar with classifications of Uncertain significance (2 clinical laboratories) and Likely benign (1 clinical laboratory); no pathogenic classifications have been submitted.
With only PM2_Supporting met and no opposing benign criteria, the variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.
No criteria match.
Met · 1
PM2 SupportingNM_003000.3:c.-8G>C is extremely rare in population databases: gnomAD v2.1 allele frequency is 0.0011% (3/271,616 alleles), v4.1 allele frequency is 0.0012% (19/1,606,996 alleles), and it is absent from gnomAD-Canada. No homozygotes have been observed. The frequency is well below the 0.1% PM2 threshold, and grpmax FAF is 3.07e-06 (v2.1) and 8.06e-06 (v4.1). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.0011%
- 3/271616 alleles
- 0 homozygotes
- gnomAD v4.1: AF=0.0012%
- 19/1606996 alleles
- gnomAD-Canada: absent.
Sources
Not met · 17 · evaluated, threshold not reached
PS2 No de novo occurrence of NM_003000.3:c.-8G>C has been reported in any publication, ClinVar submission, or variant database with confirmed parentage. Details ▾Hide ▴
Evidence considered
- Exploratory literature and database search found no de novo reports for this variant.
Still missing
- De novo status has not been assessed for any proband carrying this variant.
Sources
257418682646702520301715
PS3 No functional studies (e.g., promoter-reporter assays, RNA stability, splicing minigene, protein expression) have been identified that demonstrate a damaging effect of c.-8G>C on SDHB gene function or protein product. Details ▾Hide ▴
Evidence considered
- No functional data found in ClinVar-submitted PMIDs (25741868
- 26467025) or exploratory literature search.
Still missing
- In vitro functional characterization of the 5' UTR variant has not been performed.
Sources
2574186826467025
PS4 No case-control or cohort study has demonstrated a statistically significant enrichment of NM_003000.3:c.-8G>C in affected individuals versus controls. The variant has 3 ClinVar submissions but this is insufficient to meet PS4 thresholds. Details ▾Hide ▴
Evidence considered
- Three ClinVar submissions (2 US
- 1 LB) with no case-control statistical comparison.
Still missing
- No prevalence comparison between affected cases and general population controls.
Sources
PM1 No mutational hotspot or critical functional domain has been defined in the SDHB 5' UTR. PM1 requires a well-established critical domain without benign variation; the SDHB CSPEC v1.0.0 has not designated the 5' UTR as a hotspot region. Details ▾Hide ▴
Evidence considered
- SDHB CSPEC v1.0.0 does not define any 5' UTR hotspot. No literature supports a critical regulatory domain at c.-8.
Still missing
- The functional significance of the SDHB 5' UTR proximal region has not been systematically characterized.
Sources
PM6 No de novo observation of NM_003000.3:c.-8G>C without confirmed parentage has been reported in any publication or database. Details ▾Hide ▴
Evidence considered
- Exploratory search found no de novo reports for this variant
- ClinVar submissions lack parent-of-origin data.
Still missing
- Parental testing data unavailable for any proband carrying this variant.
Sources
2574186826467025
PP1 No cosegregation data are available for NM_003000.3:c.-8G>C. No family studies have reported this variant segregating with SDHB-related disease. Details ▾Hide ▴
Evidence considered
- No segregation studies identified in exploratory literature or database search.
Still missing
- Cosegregation has not been evaluated in any family carrying this variant.
Sources
2030171520664475243195092449372125741868263892582638927126467025
PP3 In silico prediction tools for coding variants (REVEL, BayesDel) do not score this 5' UTR variant. SpliceAI predicts no splicing impact (max delta score = 0.01). No multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.01 (no splicing impact)
- REVEL and BayesDel scores unavailable for non-coding variant
- HCI prior not supported for SDHB.
Still missing
- No 5' UTR-specific in silico predictors (e.g.
- UTRscan
- RegulomeDB) have been applied.
Sources
PP4 Individual patient phenotype and family history are not available for assessment. While SDHB-associated hereditary pheochromocytoma-paraganglioma is a clinically defined syndrome, the specificity of the proband's presentation cannot be evaluated without clinical details. Details ▾Hide ▴
Evidence considered
- One ClinVar submission lists condition as 'hereditary pheochromocytoma-paraganglioma' but provides no detailed phenotype
- other submissions list 'not provided.'
Still missing
- Detailed patient phenotype
- biochemical profile
- tumor characteristics
- and family history not available.
Sources
PP5 No reputable source has classified NM_003000.3:c.-8G>C as pathogenic. ClinVar classifications are Uncertain significance (2 clinical laboratories) and Likely benign (1 clinical laboratory). No expert panel has issued a pathogenic classification. Details ▾Hide ▴
Evidence considered
- ClinVar: 2 US
- 1 LB classifications. No submitter or expert panel classifies as pathogenic.
Sources
BA1 The population allele frequency of NM_003000.3:c.-8G>C (0.0012% in gnomAD v4.1) is far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=0.0012%
- v2.1 AF=0.0011%
- both well below 1% threshold.
Sources
BS1 The population allele frequency of NM_003000.3:c.-8G>C (0.0012% in gnomAD v4.1) is far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=0.0012%
- v2.1 AF=0.0011%
- both well below 0.3% threshold.
Sources
BS3 No functional studies have been identified demonstrating that NM_003000.3:c.-8G>C has no damaging effect on SDHB gene function, protein expression, or splicing. Details ▾Hide ▴
Evidence considered
- No in vitro or in vivo functional data available for this variant.
Still missing
- Functional characterization (e.g.
- minigene splicing assay
- promoter-reporter assay) has not been performed.
Sources
2574186826467025
BS4 No evidence of non-segregation with disease has been reported. No family studies demonstrate affected members lacking this variant or unaffected members carrying it. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data available.
Still missing
- Family studies to evaluate segregation have not been conducted for this variant.
BP2 No observation of NM_003000.3:c.-8G>C in trans with a known pathogenic SDHB variant in a healthy individual has been reported. Details ▾Hide ▴
Evidence considered
- No biallelic SDHB reports in the literature with this variant in trans.
Still missing
- No data on trans configuration with pathogenic SDHB variants.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. For NM_003000.3:c.-8G>C, only SpliceAI is available (max delta = 0.01, no splicing impact). REVEL and BayesDel scores are unavailable for this 5' UTR variant. A single benign computational predictor is insufficient to meet the BP4 threshold requiring multiple lines of evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.01 (no splicing impact) — single computational line only
- REVEL and BayesDel not applicable to non-coding variant.
Still missing
- No additional in silico predictors (conservation
- regulatory potential) have been applied.
Sources
BP5 No case has been reported in which NM_003000.3:c.-8G>C is found in an individual with an alternate molecular basis for SDHB-related disease. Details ▾Hide ▴
Evidence considered
- No co-occurrence data with another explanatory pathogenic variant available.
Still missing
- No data on co-occurrence of this variant with other pathogenic SDHB mutations.
BP6 No reputable source has classified NM_003000.3:c.-8G>C as benign. ClinVar shows Uncertain significance (2 clinical laboratories) and Likely benign (1 clinical laboratory). A single Likely benign classification from a non-expert-panel submitter does not constitute a reputable benign classification sufficient for BP6. Details ▾Hide ▴
Evidence considered
- ClinVar: US (2)
- LB (1). No expert panel or multiple-submitter benign consensus.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_003000.3:c.-8G>C is a 5' UTR substitution located 8 bp upstream of the ATG start codon. PVS1 is reserved for null variants (nonsense, frameshift, canonical +/-1,2 splice sites). This variant does not fall into any PVS1 null-variant bucket, and no functional data demonstrate an effect on protein expression that would warrant a PVS1 strength-level downgrade. Details ▾Hide ▴
Evidence considered
- Variant is a 5' UTR substitution
- not a null variant
- pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false.
Sources
PS1 N/ANo different pathogenic nucleotide change at c.-8 has been established by a reputable source. PS1 requires a known pathogenic variant at the same nucleotide position. Details ▾Hide ▴
Evidence considered
- No pathogenic variant at c.-8 position in SDHB is reported in ClinVar or the literature.
PM5 N/ANM_003000.3:c.-8G>C is a 5' UTR substitution, not a missense variant. No same-residue pathogenic missense comparators can be identified. pm5_candidates.json confirms no eligible candidates. Details ▾Hide ▴
Evidence considered
- Variant is non-coding
- pm5_candidates.json returned 0 candidates with recommendation 'not_applicable'.
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_003000.3:c.-8G>C is a 5' UTR substitution, not a missense variant. Details ▾Hide ▴
Evidence considered
- Variant is a 5' UTR substitution
- not a missense change.
BS2 N/ABS2 requires observation in a healthy adult for a disorder with full penetrance expected at an early age. SDHB-associated hereditary pheochromocytoma-paraganglioma has incomplete, age-dependent penetrance (estimated ~30% by age 80). The criterion premise of full penetrance at an early age is not satisfied for this gene-disease pair. Details ▾Hide ▴
Evidence considered
- SDHB-related PPGL has incomplete penetrance per CSPEC disease model.
Sources
BP1 N/ABP1 applies to missense variants in genes where truncating variants are a known disease mechanism. NM_003000.3:c.-8G>C is a 5' UTR substitution, not a missense variant. Details ▾Hide ▴
Evidence considered
- Variant is a 5' UTR substitution
- not a missense change.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_003000.3:c.-8G>C is a 5' UTR substitution, not a synonymous (silent) coding variant. Details ▾Hide ▴
Evidence considered
- Variant is a 5' UTR substitution
- not a synonymous coding variant.
PS5 N/ANo different pathogenic missense variant at the same residue has been established by a reputable source. Furthermore, c.-8G>C is a 5' UTR variant and does not alter a protein residue. Details ▾Hide ▴
Evidence considered
- Variant is non-coding
- no residue-level comparators exist.
Identifiers
- Gene
- SDHB
- Transcript
- NM_003000.3
- Coding (HGVS c.)
- NM_003000.3:c.-8G>C
- Protein (HGVS p.)
- NP_002991.2:p.?
- GRCh38
- chr1:17054027 C>G
- GRCh37
- chr1:17380522 C>G
- ClinVar
- 3572228
Gene diagram
Every interpreted variant in SDHB, mapped onto the exon structure of NM_003000.3. Select a row to find it on the plot.
SDHBNM_003000.3
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in SDHB
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
19 / 1,606,996 alleles
AF 1.18e-05 · 0 homozygotes · FAF 8.06e-06
gnomAD v2.1
3 / 271,616 alleles
AF 1.1e-05 · 0 homozygotes · FAF 3.07e-06
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 1.2e-05 · 19 / 1,606,996 alleles · 0 hom · FAF 8.1e-06
| Remaining individuals3 / 62,170 | 4.8e-05 |
| European (non-Finnish)16 / 1,175,624 | 1.4e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.1e-05 · 3 / 271,616 alleles · 0 hom · FAF 3.1e-06
| European (non-Finnish)3 / 123,516 | 2.4e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.18233e-05; MAF= 0.00118%, 19/1606996 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.82548e-05; MAF= 0.00483%, 3/62170 alleles, homozygotes = 0); grpmax FAF= 8.06e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.1045e-05; MAF= 0.00110%, 3/271616 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.42884e-05; MAF= 0.00243%, 3/123516 alleles, homozygotes = 0); grpmax FAF= 3.07e-06.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 In silico prediction tools for coding variants (REVEL, BayesDel) do not score this 5' UTR variant. SpliceAI predicts no splicing impact (max delta score = 0.01). No multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.01 (no splicing impact)
- REVEL and BayesDel scores unavailable for non-coding variant
- HCI prior not supported for SDHB.
Still missing
- No 5' UTR-specific in silico predictors (e.g.
- UTRscan
- RegulomeDB) have been applied.
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. For NM_003000.3:c.-8G>C, only SpliceAI is available (max delta = 0.01, no splicing impact). REVEL and BayesDel scores are unavailable for this 5' UTR variant. A single benign computational predictor is insufficient to meet the BP4 threshold requiring multiple lines of evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.01 (no splicing impact) — single computational line only
- REVEL and BayesDel not applicable to non-coding variant.
Still missing
- No additional in silico predictors (conservation
- regulatory potential) have been applied.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_003000.3:c.-8G>C is a 5' UTR substitution, not a synonymous (silent) coding variant. Details ▾Hide ▴
Evidence considered
- Variant is a 5' UTR substitution
- not a synonymous coding variant.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
10 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015No paper-specific finding is recorded.
-
PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi I et al. · 2016No paper-specific finding is recorded.
-
PMID 20301715 ↗Hereditary Paraganglioma-Pheochromocytoma Syndromes.Adam MP et al. · 1993No paper-specific finding is recorded.
-
PMID 20664475 ↗The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer.Chen H et al. · 2010No paper-specific finding is recorded.
-
PMID 24319509 ↗Canadian guideline on genetic screening for hereditary renal cell cancers.Reaume MN et al. · 2013No paper-specific finding is recorded.
-
PMID 24493721 ↗American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.Lu KH et al. · 2014No paper-specific finding is recorded.
-
PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
-
PMID 26389271 ↗Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
-
PMID 24893135 ↗Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.Lenders JW et al. · 2014No paper-specific finding is recorded.
-
PMID 33939658 ↗The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.Fishbein L et al. · 2021No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
19 / 1,606,996 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
2 Uncertain significance · 1 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/101200173
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3572228/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-17380522-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-17054027-C-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003000.3%3Ac.-8G%…
- OncoKB ↗www.oncokb.org/gene/SDHB/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SDHB+c.-8G%3EC
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.18233e-05; MAF= 0.00118%, 19/1606996 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.82548e-05; MAF= 0.00483%, 3/62170 alleles, homozygotes = 0); grpmax FAF= 8.06e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.1045e-05; MAF= 0.00110%, 3/271616 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.42884e-05; MAF= 0.00243%, 3/123516 alleles, homozygotes = 0); grpmax FAF= 3.07e-06.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 3572228)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).