Variant classification summary

NM_000053.4:c.3207C>A

ATP7B · NP_000044.2:p.(His1069Gln) · NM_000053.4

GRCh37: chr13:52518281 G>T · GRCh38: chr13:51944145 G>T

Gene: ATP7B Transcript: NM_000053.4

Final call

Pathogenic

PS3 strong PS4 strong PP3 supporting

Variant details

Gene

ATP7B

Transcript

NM_000053.4

Protein

NP_000044.2:p.(His1069Gln)

gnomAD AF

0.0009435212983051309 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PS3 strong from concordant biochemical and cellular functional defects.

2

Pathogenic evidence: PS4 strong from marked enrichment in affected patients versus NFE gnomAD.

3

Pathogenic evidence: PP3 supporting from REVEL 0.909.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS3 and PS4) satisfy the Pathogenic combination rule; PP3 supporting is additional evidence.

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: ClinVar establishes c.3207C>A as pathogenic, but no pathogenic alternate nucleotide change producing the same p.His1069Gln substitution is documented.	clinvar
PS2	Not assessed	Not assessed: no documented de novo occurrence with confirmed maternity and paternity, absence of family history, and a qualifying affected proband.	PMID:11857545
PS3	Met	Met, strong: four independent assays showed impaired ATP binding, with H1069Q failing to saturate even at 600 µM ATP and showing concordant cellular dysfunction.	PMID:15205462 PMID:18692069 PMID:19937698 PMID:21398519
PS4	Met	Met: H1069Q occurred in 27/42 affected patients versus 0.1058% in NFE gnomAD, yielding OR 1,698.8 (95% CI 901.5-3,201.2), above the >5.0 threshold.	PMID:11857545 gnomad_v4
PM1	Not assessed	Not assessed: His1069 lies within the ATP7B nucleotide-binding domain (residues 1036–1196), but absence of benign variation across that domain is not established.	PMID:15205462 PMID:18692069
PM2	Not met	Not met: gnomAD v4.1 AF is 0.000943521, exceeding the 0.0001 PM2 threshold, with one observed homozygote.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: 18 compound-heterozygous affected patients were reported, but parental/offspring phase testing and pathogenicity of the partner alleles are not documented.	PMID:11857545 PMID:25741868
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: the variant is p.His1069Gln, but no independently pathogenic different missense change at residue 1069 is documented.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no documented assumed de novo occurrence or parental testing information is available for this variant.	PMID:11857545
PP1	Not assessed	Not assessed: 27 of 42 affected patients carried H1069Q, but no affected-relative co-segregation or informative meioses were reported.	PMID:11857545
PP2	Not assessed	Not assessed: ATP7B missense disease variants are documented, but no gene-level evidence establishes both low benign missense variation and a common missense mechanism.	gnomad_v2 gnomad_v4
PP3	Met	Met, supporting: missense REVEL score 0.909 exceeds the PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history is provided to determine whether it is highly specific for Wilson disease.
PP5	Not met	Not met: ClinVar lists H1069Q as Pathogenic but has 0 expert-panel submissions, so the required expert-panel trigger is absent.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.0010095, far below the 0.05 BA1 threshold, with 29,608 Ashkenazi Jewish observed alleles.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.0010095, below the generic 0.01 BS1 threshold, so ancestry-specific point estimates cannot establish BS1.	gnomad_v4 gnomad_v2 clinvar
BS2	Not assessed	Not assessed: gnomAD v4.1 has one homozygote, but no age, health, or phenotype evidence confirms a qualifying healthy adult.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: no reviewed assay showed normal function; instead, H1069Q caused reduced ATP binding, protein instability, mislocalization, and impaired copper export.	PMID:15205462 PMID:18692069 PMID:19937698 PMID:21398519
BS4	Not assessed	Not assessed: no affected-family-member non-segregation data or pedigree analysis is available for this variant.
BP1	Not met	Not met: the reported ATP7B spectrum included seven missense but only two nonsense and three splice-site mutations, not primarily truncating disease variants.	PMID:7626145
BP2	Not met	Not met: affected-patient data show homozygous or compound-heterozygous observations, with no documented cis occurrence with a pathogenic variant.	PMID:11857545 PMID:25741868
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	Not met	Not met: missense REVEL score 0.909 is above the BP4 supporting threshold of 0.29.	revel
BP5	Not assessed	Not assessed: no evidence shows this exact variant in a case where an alternate molecular basis explains the disease.
BP6	Not met	Not met: ClinVar has no exact-variant Benign/Likely benign expert-panel classification and instead reports Pathogenic.	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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