Variant classification summary

NM_000049.4:c.854A>C

ASPA · NP_000040.1:p.(Glu285Ala) · NM_000049.4

GRCh37: chr17:3402294 A>C · GRCh38: chr17:3499000 A>C

Gene: ASPA Transcript: NM_000049.4

Final call

Likely Pathogenic

PS3 moderate PS4 strong PM3 supporting PP3 strong

Variant details

Gene

ASPA

Transcript

NM_000049.4

Protein

NP_000040.1:p.(Glu285Ala)

gnomAD AF

0.00022055634719038474 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 moderate: E285A retained only 0.3% of native ASPA activity.

2

PS4 strong: 18/18 affected individuals versus 15/879 controls produced OR 2063.65 with a confidence interval excluding 1.

3

PM3 supporting: E285A was observed in trans with IVS4+1G>T in an affected patient.

4

PP3 strong: REVEL 0.946 exceeds the strong threshold of 0.932.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus one moderate pathogenic criterion supports a Likely Pathogenic call; PM3 and PP3 provide additional supporting-direction 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: p.Glu285Ala is established as pathogenic, but no pathogenic alternate nucleotide change producing the same amino-acid change is documented.	PMID:22850825 PMID:16854607 clinvar
PS2	Not assessed	Not assessed: no documented maternity and paternity confirmation, parental testing, or absence of family history is available for the proband.
PS3	Met	Met, moderate: purified E285A showed 0.02 U/mg activity, only 0.3% of native ASPA activity in a variant-specific assay.	PMID:22850825 PMID:25741868
PS4	Met	Met: 18/18 affected patients versus 15/879 controls; continuity-corrected OR 2063.65 (95% CI 118.94-35805.20), exceeding the OR > 5 threshold with CI excluding 1.
PM1	Not assessed	Not assessed: p.Glu285Ala is predicted in ASPA's catalytic domain, but absence of benign variation in that domain is not established.	PMID:8252036
PM2	Not met	Not met: gnomAD v4.1 total AF is 0.000220556, exceeding the PM2 threshold of 0.0001, with the variant also present in gnomAD v2.1.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	Met	Met at supporting strength: an affected Canavan disease patient carried c.854A>C compound heterozygously with IVS4+1G>T, documenting an in-trans pathogenic partner.	PMID:16854607
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 comparator record contains 0 same-residue candidates, and no different pathogenic missense change at Glu285 is documented.	pm5_candidates
PM6	Not assessed	Not assessed: affected carriers are reported, but no assumed de novo event or parental-origin evidence is documented.
PP1	Not assessed	Not assessed: reports from unrelated families provide no documented multiple-affected-relative cosegregation or informative segregation count.	PMID:16854607
PP2	Not assessed	Not assessed: recurrent pathogenic missense variation is documented, but low benign missense variation and a common missense mechanism are not both established.	PMID:22850825
PP3	Met	Met strong: missense REVEL score 0.946 meets the PP3 strong threshold of >=0.932.	revel
PP4	Not assessed	Not assessed: the patient's detailed phenotype and family history are unavailable, so specificity for Canavan disease cannot be judged.
PP5	Not met	Not met: ClinVar has no expert-panel classification for the exact variant; its Pathogenic/Likely pathogenic submissions are non-expert assertions.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00002585, far below the BA1 threshold of 0.05 despite an Ashkenazi Jewish popmax AF of 0.009256.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00002585, below the generic BS1 threshold of 0.01; the 0.9256% Ashkenazi Jewish popmax is not used.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v4.1 and v2.1 each report zero homozygotes, so no healthy-adult homozygous observation supports BS2 for this recessive disorder.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: E285A retained only 0.3% of native ASPA activity, indicating damage rather than preserved protein function.	PMID:22850825 PMID:25741868
BS4	Not assessed	Not assessed: no tested affected relatives lacking the variant or informative family non-segregation analysis is documented.
BP1	Not met	Not met: ASPA's E285A missense founder variant contributes to 97% of Ashkenazi Jewish mutant alleles with Y231X, contradicting a primarily truncating spectrum.	PMID:16854607 PMID:22850825
BP2	Not met	Not met: the reported E285A/IVS4+1G>T genotype is trans in a recessive disorder, whereas BP2 requires dominant-disorder trans or any-disorder cis evidence.	PMID:16854607
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 0.946 exceeds the BP4 strong threshold of <=0.016 and is not in any benign calibration range.	revel
BP5	Not assessed	Not assessed: no case is documented with c.854A>C plus an independent alternate molecular basis for disease.
BP6	Not met	Not met: ClinVar contains no exact-variant expert-panel Benign or Likely benign classification for c.854A>C.	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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