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.1 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.2 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.3
SDHB
Final classification
VUS
SDHB c.-8G>C · p.?
SDHB
NM_003000.3:c.-8G>C is a 5' UTR substitution located 8 bp upstream of the ATG start codon in SDHB.
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.
Classification rationale
PM2
VUS
SDHB c.-8G>C
PM2
→
VUS
Gene diagram
· NM_003000.3 · variants mapped to exon structure
SDHB
NM_003000.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 17 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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).
gnomAD v2.1: AF=0.0011%3/271616 alleles0 homozygotes
Assessed · not applied
Pathogenic
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.
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.
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.
PM1
No mutational hotspot or critical functional domain has been defined in the SDHB 5' UTR.
PM6
No de novo observation of NM_003000.3:c.-8G>C without confirmed parentage has been reported in any publication or database.
PP1
No cosegregation data are available for NM_003000.3:c.-8G>C.
PP3
In silico prediction tools for coding variants (REVEL, BayesDel) do not score this 5' UTR variant.
PP4
Individual patient phenotype and family history are not available for assessment.
PP5
No reputable source has classified NM_003000.3:c.-8G>C as pathogenic.
Benign
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%.
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%.
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.
BS4
No evidence of non-segregation with disease has been reported.
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.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product.
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.
BP6
No reputable source has classified NM_003000.3:c.-8G>C as benign.
N/A · 7
PVS1 · PS1 · PM5 · PP2 · BS2 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0012%
· 19 / 1,606,996
0 hom · FAF 0.00081%
0 hom · FAF 0.00081%
Remaining individuals 3 / 62,170 |
0.0048% |
European (non-Finnish) 16 / 1,175,624 |
0.0014% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0011%
· 3 / 271,616
0 hom · FAF 0.00031%
0 hom · FAF 0.00031%
European (non-Finnish) 3 / 123,516 |
0.0024% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 10 PMIDs not cited in assessment
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.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
20664475 ↗
The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer.
CLINVAR
24493721 ↗
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
26389271 ↗
Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®): Health Professional Version.
CLINVAR
24893135 ↗
Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
CLINVAR
33939658 ↗
The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.
CLINVAR