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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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