LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-02
Case ID: NM_000016.6_c.985A_G_20261102_071531
Framework: ACMG/AMP 2015
Variant classification summary

NM_000016.6:c.985A>G

ACADM  · NP_000007.1:p.(Lys329Glu)  · NM_000016.6
GRCh37: chr1:76226846 A>G  ·  GRCh38: chr1:75761161 A>G
Gene: ACADM Transcript: NM_000016.6
Final call
Pathogenic
PS3 strong PS4 strong PM3 supporting PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
ACADM
Transcript
NM_000016.6
Protein
NP_000007.1:p.(Lys329Glu)
gnomAD AF
0.005822533539354453 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS3 strong reflects 0–8% residual MCAD activity in homozygous newborns and concordant abnormal protein assays.
2
Pathogenic: PS4 strong reflects an affected-case versus control OR of 1053.0 with a 95% CI excluding 1.
3
Pathogenic: PM3 supporting reflects homozygous affected individuals and parental heterozygosity consistent with recessive phase evidence.
4
Pathogenic: PP3 supporting reflects REVEL 0.695 meeting the generic missense threshold.
Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS3 and PS4) satisfy the Pathogenic combination rule; PM3 and PP3 are additional supporting criteria.
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: reviewed sources establish p.Lys329Glu from c.985A>G but provide no pathogenic alternate-nucleotide change producing the same amino-acid substitution.
PMID:2393404 PMID:24718418 clinvar
PS2 Not assessed Not assessed: no documented affected proband with confirmed maternity and paternity; one reported family had both parents heterozygous for the variant.
PMID:2393404
PS3 Met Met, strong: homozygous c.985A>G newborns showed 0–8% residual MCAD activity, with concordant protein misfolding and reduced activity in independent assays.
PMID:23028790 PMID:19224950 PMID:24718418
PS4 Met Met: reported affected-case versus normal-control counts give a continuity-corrected OR of 1053.0 (95% CI 52.7-21039), exceeding the >5.0 threshold with the CI excluding 1.
PMID:2393404 PMID:23151387
PM1 Not assessed Not assessed: no authoritative ACADM critical-domain specification or benign-variation exclusion was available, and Cancer Hotspots found no statistically significant hotspot.
PMID:24718418 hotspots cosmic
PM2 Not met Not met: gnomAD v4.1 AF is 0.00582253, far above the PM2 threshold of 0.0001, with 19 homozygotes reported.
gnomad_v4 gnomad_v2 PMID:2393404
PM3 Met Met at supporting strength: affected individuals were homozygous and both parents were heterozygous, establishing two variant copies in trans for recessive MCADD.
PMID:2393404 PMID:23028790
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 reliably pathogenic different missense substitution at ACADM Lys329 was identified; the PM5 candidate set contained zero same-residue candidates.
pm5_candidates PMID:2393404 PMID:24718418
PM6 Not assessed Not assessed: no case-level assumed de novo occurrence is documented; the reported tested parents were both heterozygous.
PMID:2393404
PP1 Not assessed Not assessed: multiple affected relatives with documented co-segregation and informative meioses are not reported for this variant.
PMID:2393404
PP2 Not assessed Not assessed: ACADM missense disease mechanism is supported, but no gene-level evidence establishing a low rate of benign missense variation was supplied.
PMID:2393404 PMID:24718418
PP3 Met Met at supporting: REVEL 0.695 meets the generic PP3 supporting threshold of >= 0.644 for this missense variant.
revel
PP4 Not assessed Not assessed: no patient-specific phenotype or family-history information is available to determine whether the presentation is highly specific for MCAD deficiency.
PP5 Not met Not met: ClinVar has zero expert-panel submissions, and the published evidence supporting pathogenicity is available for independent evaluation rather than being unavailable.
clinvar PMID:2393404
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.0073482, below the generic BA1 stand-alone threshold of 0.05.
gnomad_v4 gnomad_v2
BS1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.0073482, below the generic BS1 frequency threshold of 0.01.
gnomad_v4 gnomad_v2
BS2 Not assessed Not assessed: gnomAD reports 19 homozygotes, but no evidence shows they were healthy adults with expected early-onset full penetrance.
gnomad_v4 gnomad_v2
BS3 Not met Not met: available assays show 0–8% residual activity in homozygotes and 46% recombinant activity, rather than no damaging effect.
PMID:23028790 PMID:19224950 PMID:24718418
BS4 Not assessed Not assessed: no affected family members with negative variant testing are documented for a valid non-segregation comparison.
PMID:2393404
BP1 Not assessed Not assessed: available evidence documents disease-associated ACADM missense variants but does not establish that disease is caused primarily by truncating variants.
PMID:2393404 PMID:24718418
BP2 Not assessed Not assessed: no phase-resolved cis observation with a pathogenic variant is available, and the reported trans observations are for recessive PM3 rather than BP2.
PMID:2393404 PMID:23028790
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: REVEL 0.695 exceeds the generic BP4 supporting threshold of <= 0.29 for this missense variant.
revel
BP5 Not assessed Not assessed: no case carrying the variant is documented with an alternate molecular basis for the disease.
BP6 Not met Not met: no exact-variant ClinVar expert-panel benign or likely-benign classification is present; the available submissions are pathogenic or likely 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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