Variant classification summary

NM_000754.4:c.472G>A

COMT · NP_000745.1:p.(Val158Met) · NM_000754.4

GRCh37: chr22:19951271 G>A · GRCh38: chr22:19963748 G>A

Gene: COMT Transcript: NM_000754.4

Final call

Benign

PS3 supporting PS4 strong BA1 stand-alone benign BS1 strong BP4 supporting BP5 supporting

Variant details

Gene

COMT

Transcript

NM_000754.4

Protein

NP_000745.1:p.(Val158Met)

gnomAD AF

0.49047984463781935 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: Met158 has approximately three- to fourfold lower COMT activity than Val158.

2

PS4 strong: the rapid-cycling bipolar subgroup had OR 25.20 with 95% CI 1.43–443.62.

3

BA1 stand-alone benign: gnomAD v4.1 filtering grpmax FAF is 0.515321, above 0.05.

4

BS1 strong: gnomAD v4.1 filtering grpmax FAF is 0.515321, above 0.01.

5

BP4 supporting: REVEL 0.065 is at or below the 0.29 benign threshold.

6

BP5 supporting: the variant occurred in VCFS cases primarily explained by 22q11.2 deletion.

Final determination: Under generic ACMG/AMP 2015 fallback rules, BA1 alone yields Benign; benign evidence therefore prevails, and PS4 strong plus PS3 supporting does not satisfy a pathogenic rule.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no previously established pathogenic variant with the same COMT p.Val158Met amino-acid change was identified.	PMID:10459407 PMID:8886163 clinvar
PS2	Not assessed	Not assessed: no proband phenotype, confirmed maternity and paternity, de novo test, or family-history information is documented.
PS3	Met	Met: variant-specific studies report approximately three- to fourfold lower COMT enzymatic activity for Met158 than Val158, but assay validation and controls are incompletely documented.	PMID:10459407 PMID:8886163
PS4	Met	Met: rapid-cycling bipolar subgroup OR 25.20, 95% CI 1.43–443.62, exceeds the >5.0 threshold and excludes 1.	PMID:8886163 PMID:8941353
PM1	Not met	Not met: no established COMT hotspot or critical domain without benign variation was documented, and Cancer Hotspots returned no COMT V158 result.	hotspots cosmic
PM2	Not met	Not met: gnomAD v4.1 AF is 0.490480, vastly exceeding the <=0.0001 PM2 supporting threshold.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected-proband observation, pathogenic variant in trans, recessive disorder context, parental testing, or phase information was established.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense variant at COMT residue 158 was documented for comparison with p.Val158Met.	pm5_candidates PMID:10459407 PMID:8886163
PM6	Not assessed	Not assessed: no assumed de novo occurrence or parental testing result is documented for a disease-affected proband.
PP1	Not assessed	Not assessed: no affected relatives, disease-linked genotypes, pedigree, or meioses are documented for segregation analysis.	PMID:7304673
PP2	Not met	Not met: COMT p.Val158Met has gnomAD v4.1 allele frequency 0.49048 with 197380 homozygotes, inconsistent with low benign missense variation.	gnomad_v4 PMID:10459407 clinvar
PP3	Not met	Not met: missense REVEL 0.065 is below the PP3 supporting threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: reviewed cohorts provide no index-patient phenotype specific for a single-etiology COMT c.472G>A disorder.	PMID:8886163 PMID:16542388
PP5	Not met	Not met: ClinVar has zero expert-panel submissions for the exact variant and no expert-panel Pathogenic/Likely pathogenic classification.	clinvar
BA1	Met	Met: gnomAD v4.1 grpmax FAF is 0.515321, exceeding the 0.05 BA1 threshold with 1,610,688 observed alleles.	gnomad_v4 gnomad_v2 clinvar
BS1	Met	Met: gnomAD v4.1 grpmax FAF is 0.515321, far above the 0.01 generic BS1 threshold in a large population dataset.	gnomad_v4 gnomad_v2 clinvar
BS2	Not assessed	Not assessed: gnomAD reports 197,380 homozygotes, but no specific COMT disorder with expected early full penetrance is established for applying BS2.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: reviewed studies report approximately three- to fourfold reduced COMT activity for Met158 rather than no damaging effect on protein function or splicing.	PMID:10459407 PMID:8886163
BS4	Not assessed	Not assessed: no affected-family genotypes and phenotypes are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: no reliable gene-level evidence showed that COMT disease is caused primarily by truncating rather than missense variants.
BP2	Not assessed	Not assessed: no phase-resolved pathogenic variant in trans or cis, affected-proband observation, or fully penetrant dominant COMT disorder was established.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting: missense REVEL 0.065 meets the BP4 threshold of <=0.29.	revel
BP5	Met	Met: the exact variant was observed in VCFS cases primarily explained by 22q11.2 deletion, an alternate molecular basis for the disease.	PMID:8886163
BP6	Not met	Not met: the exact variant lacks a ClinVar expert-panel Benign/Likely benign classification; available assertions are non-expert records.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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