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
Population frequency
Overall AF
19 / 1,606,996
0.0012%
Highest · Remaining individuals
0.0048%
Homozygotes
0
grpmax FAF
0.00081%
Allele frequency by ancestry — gnomAD v4.1
observed in 1 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 16 / 1,175,624 | 0.0014% | 0 |
| Admixed American | 0 / 59,818 | — | — |
| European (Finnish) | 0 / 63,214 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,772 | — | — |
| Middle Eastern | 0 / 5,828 | — | — |
| South Asian | 0 / 90,412 | — | — |
| Ashkenazi Jewish | 0 / 29,470 | — | — |
| African/African American | 0 / 74,776 | — | — |
“
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.
Overall AF
3 / 271,616
0.0011%
Highest · European (non-Finnish)
0.0024%
Homozygotes
0
grpmax FAF
0.00031%
Allele frequency by ancestry — gnomAD v2.1
observed in 1 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 3 / 123,516 | 0.0024% | 0 |
| African/African American | 0 / 23,736 | — | — |
| Admixed American | 0 / 34,946 | — | — |
| Ashkenazi Jewish | 0 / 10,094 | — | — |
| East Asian | 0 / 19,492 | — | — |
| European (Finnish) | 0 / 23,096 | — | — |
| Remaining individuals | 0 / 6,952 | — | — |
| South Asian | 0 / 29,784 | — | — |
“
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.
“
This variant is absent from gnomAD-Canada.
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.
Literature · 10 PMIDs triaged · 8 high-priority
10papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
25741868 ↗
functional
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.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PP5PS3PS4
26467025 ↗
functional
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies
BS3PP5PS3PS4
20664475 ↗
case observation
The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer.
Pheochromocytomas, intra-adrenal paraganglioma, and extra-adrenal sympathetic and parasympathetic paragangliomas are neuroendocrine tumors derived from adrenal chromaffin cells or similar cells in extra-adrenal sympathetic and parasympathetic paraganglia, respectively. Serious morbidity and mortality rates associated with these tumors are related to the potent effects of catecholamines on various
PP5PS4
24319509 ↗
case observation
Canadian guideline on genetic screening for hereditary renal cell cancers.
Hereditary renal cell cancer (RCC) is an ideal model for germline genetic testing. We propose a guideline of hereditary RCC specific criteria to suggest referral for genetic assessment. A review of the literature and stakeholder resources for existing guidelines or consensus statements was performed. Referral criteria were developed by expert consensus. The criteria included characteristics for pa
PP5PS4
24493721 ↗
case observation
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
PP5PS4
24893135 ↗
background review
Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
PP5PS4
33939658 ↗
background review
The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.
PP5PS4
Sources & reference links