Variant classification summary

NM_003000.3:c.178A>G

SDHB · NP_002991.2:p.(Thr60Ala) · NM_003000.3

GRCh37: chr1:17371278 T>C · GRCh38: chr1:17044783 T>C

Gene: SDHB Transcript: NM_003000.3

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

SDHB

Transcript

NM_003000.3

Protein

NP_002991.2:p.(Thr60Ala)

gnomAD AF

9.665595190003296e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): variant is rare in population databases - gnomAD v4.1 overall AF 0.009666%, zero homozygotes, below the 0.1% threshold.

2

PP3 (Moderate): REVEL 0.845 exceeds the >=0.773 moderate pathogenic-evidence threshold.

3

Synthesis: PM2 (supporting) plus PP3 (moderate) does not meet the ACMG/AMP 2015 combination thresholds for Likely Pathogenic or Likely Benign; the variant is classified as VUS.

Final determination: Generic ACMG/AMP 2015 fallback: 1 moderate (PP3) + 1 supporting (PM2) meets no Pathogenic/LP/Benign/LB threshold → VUS.

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	Not applicable: missense substitution; PVS1 applies only to null variants such as nonsense, frameshift, and canonical splice-site changes.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no independent pathogenic classification of the same amino-acid change (p.Thr60Ala) from a different nucleotide substitution.	clinvar
PS2	Not assessed	Not assessed: no documented de novo occurrence; the maternal-origin ClinVar submission lacks parental genotypes and identity testing.	cspec clinvar PMID:25741868
PS3	Not assessed	Not assessed: no functional assay data for p.Thr60Ala; the large SDHB functional study (PMID:41252211) does not report this variant.
PS4	Not assessed	Not assessed: no case-control enrichment analysis or series of unrelated affected individuals with this exact variant.	cspec clinvar PMID:25741868
PM1	Not met	Not met: residue Thr60 is not among SDHB's Fe-S cluster-coordinating cysteines or other residues flagged as structurally critical.	cspec PMID:41252211
PM2	Met	Met (supporting): gnomAD v4.1 overall AF 0.009666% (NFE 0.011865%), zero homozygotes, below the 0.1% rarity threshold.	gnomad_v4 gnomad_v2 gnomad_canada cspec PMID:25741868
PM3	N/A	Not applicable: the SDHB-associated disease model is autosomal dominant, so no recessive trans configuration exists to evaluate.	cspec clinvar
PM4	N/A	Not applicable: missense substitution causes no protein length change; PM4 requires an in-frame indel or stop-loss variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: the only alternate residue-60 variant (p.Thr60Ile) was functionally reclassified as Likely Benign, not pathogenic.	PMID:41252211 pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo occurrence; reported maternal origin argues against a de novo event.	cspec clinvar PMID:25741868
PP1	Not assessed	Not assessed: no pedigree, affected-relative genotypes, or informative meioses are provided.	cspec clinvar PMID:25741868
PP2	Not assessed	Not assessed: no missense constraint statistics or benign-missense-rate data were available to establish both PP2 requirements.	cspec
PP3	Met	Met (moderate): REVEL 0.845 meets the ClinGen SVI-calibrated moderate pathogenic-evidence threshold (>=0.773).	revel spliceai cspec
PP4	Not assessed	Not assessed: no proband phenotype or family-history information supplied, so phenotype specificity cannot be evaluated.	cspec PMID:25741868
PP5	Not met	Not met: no ClinVar expert-panel Pathogenic or Likely pathogenic classification exists for this exact variant.	clinvar
BA1	Not met	Not met: highest population frequency NFE AF 0.011865% (140/1,179,932 alleles), far below the 1% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada cspec PMID:25741868
BS1	Not met	Not met: highest robust population frequency NFE AF 0.011865%, below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada cspec PMID:25741868
BS2	Not assessed	Not assessed: zero homozygotes in population databases, but no phenotype-verified unaffected adult carriers were available.	gnomad_v4 gnomad_v2 gnomad_canada cspec
BS3	Not assessed	Not assessed: no functional assay evidence of normal SDHB activity for p.Thr60Ala was identified.
BS4	Not assessed	Not assessed: no affected family member documented to lack the variant; maternal origin alone does not establish non-segregation.	cspec clinvar PMID:25741868
BP1	N/A	Not applicable: missense variation is a well-established pathogenic mechanism in SDHB, so BP1's rarely-missense premise fails.	PMID:41252211
BP2	Not assessed	Not assessed: no qualifying co-occurrence with an established pathogenic SDHB variant is documented.	cspec clinvar
BP3	N/A	Not applicable: missense substitution; BP3 requires an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.845 far exceeds the <=0.290 BP4 benign threshold, supporting a pathogenic direction.	revel spliceai cspec
BP5	Not assessed	Not assessed: no molecular testing result documents an alternate molecular basis for disease.	PMID:25741868
BP6	Not met	Not met: no ClinVar expert-panel Benign or Likely benign classification exists for this exact variant.	clinvar
BP7	N/A	Not applicable: missense substitution; BP7 is defined for synonymous variants with no predicted splice impact.	generic_acmg_combination_rules

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