Variant classification summary

NM_003000.3:c.-8G>C

SDHB · NP_002991.2:p.? · NM_003000.3

GRCh37: chr1:17380522 C>G · GRCh38: chr1:17054027 C>G

Gene: SDHB Transcript: NM_003000.3

Final call

VUS

PM2 supporting

Variant details

Gene

SDHB

Transcript

NM_003000.3

Protein

NP_002991.2:p.?

gnomAD AF

1.1823302609340658e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_003000.3:c.-8G>C is a 5' UTR substitution located 8 bp upstream of the ATG start codon in SDHB.

2

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.

3

No functional studies, case-control data, segregation data, de novo observations, or computational evidence are available to support any additional pathogenic or benign criteria.

4

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.

5

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_generic_framework
PS1	N/A	No 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.
PS2	Not met	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	Not met	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	Not met	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.	clinvar
PS5	N/A	No 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.
PM1	Not met	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.	cspec
PM2	Met	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 gnomad_v4
PM5	N/A	NM_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.
PM6	Not met	No de novo observation of NM_003000.3:c.-8G>C without confirmed parentage has been reported in any publication or database.
PP1	Not met	No cosegregation data are available for NM_003000.3:c.-8G>C. No family studies have reported this variant segregating with SDHB-related disease.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	Not met	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.	clinvar
PP5	Not met	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.	clinvar
BA1	Not met	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%.	gnomad_v2 gnomad_v4
BS1	Not met	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%.	gnomad_v2 gnomad_v4
BS2	N/A	BS2 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.	cspec
BS3	Not met	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	Not met	No evidence of non-segregation with disease has been reported. No family studies demonstrate affected members lacking this variant or unaffected members carrying it.
BP1	N/A	BP1 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.
BP2	Not met	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	Not met	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.	spliceai
BP5	Not met	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	Not met	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.	clinvar
BP7	N/A	BP7 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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.