Variant classification summary

NM_000277.3:c.1222C>T

PAH · NP_000268.1:p.(Arg408Trp) · NM_000277.3

GRCh37: chr12:103234271 G>A · GRCh38: chr12:102840493 G>A

Gene: PAH Transcript: NM_000277.3

Final call

Likely Benign

PS3 supporting PP3 moderate PP5 supporting BS1 strong BP4 supporting BP7 supporting

Variant details

Gene

PAH

Transcript

NM_000277.3

Protein

NP_000268.1:p.(Arg408Trp)

gnomAD AF

0.0013237022017084186 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: p.Arg408Trp retained only 1.85% of wild-type PAH activity.

2

PP3 moderate: REVEL score 0.887 falls within the VCEP moderate interval.

3

PP5 supporting: the adjudicated assessment records an expert-panel pathogenic classification.

4

BS1 strong: gnomAD v2.1 maximum population frequency 0.0027554 exceeds the VCEP threshold of 0.002.

5

BP4 supporting: maximum SpliceAI delta score 0.092 is below 0.1.

6

BP7 supporting: BP4 is met and the variant is outside the exon-12 edge bases.

Final determination: Under the PAH VCEP Version 2.0 framework, Rule18 is satisfied by one strong benign criterion (BS1) and one supporting benign criterion (BP4), yielding Likely Benign; BP7 also independently contributes to Rule19.

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: c.1222C>T is a missense variant, whereas the PAH VCEP PVS1 rule names nonsense, frameshift, splice-site, initiator-codon, or RNA-evidence paths.	cspec
PS1	Not assessed	Not assessed: SpliceAI maximum delta is 0.092, but no qualifying previously classified comparator with the same predicted splicing impact is documented.	cspec spliceai
PS2	Not assessed	Not assessed: no documented de novo finding with confirmed maternity, paternity, and a known pathogenic variant in trans.
PS3	Met	Met at supporting: p.Arg408Trp PAH activity was 1.85% of wild type, below the VCEP PS3 threshold of 50%.	vcep_ps3_functional_assay_pah PMID:17935162
PS4	N/A	Not applicable: the PAH VCEP explicitly excludes PS4 and directs proband counting to PM3.	cspec PMID:17935162 PMID:18937047
PM1	Not met	Not met: residue 408 lies outside every PAH VCEP-listed active-, substrate-, and cofactor-binding PM1 region, whose highest listed boundary is 379.	cspec revel PMID:17935162 PMID:18538294
PM2	Not met	Not met: gnomAD v2.1 total AF is 0.000890988, above the VCEP PM2 cutoff of <0.0002 (0.02%).	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no documented pathogenic PAH allele in trans or parental/offspring phase testing is available for the affected proband.	cspec
PM4	N/A	Not applicable: p.(Arg408Trp) is a missense substitution and does not produce a protein-length change, in-frame indel, or stop-loss consequence.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: the Arg408 comparator search found zero same-residue candidates and no qualifying pathogenic or likely pathogenic alternative missense change.	cspec pm5_candidates
PM6	N/A	Not applicable: the PAH VCEP explicitly marks PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: ClinVar gives no segregation counts, while the VCEP requires defined affected and unaffected segregation totals.	clinvar cspec
PP2	N/A	Not applicable: the PAH VCEP explicitly marks PP2 not applicable for this framework.	cspec
PP3	Met	Met at Moderate: REVEL score 0.887 falls within the VCEP PP3 missense interval of 0.773–0.932.	cspec revel
PP4	Not assessed	Not assessed: no persistent plasma phenylalanine value above 120umol/L or BH4-pathway exclusion results are documented.	cspec
PP5	Met	Not applicable: the PAH VCEP prohibits PP5 use regardless of pathogenic assertions from reputable sources.	cspec clinvar
BA1	Not met	Not met: the highest reported population frequency is 0.0027554, below the VCEP BA1 threshold of 0.015 (1.5%).	cspec gnomad_v2 gnomad_v4
BS1	Met	Met at strong: gnomAD v2.1 grpmax FAF is 0.0027554, exceeding the VCEP BS1 threshold of 0.002 (0.2%).	cspec gnomad_v2
BS2	Not met	Not met: gnomAD v2.1 and v4.1 each report zero homozygotes, so no qualifying healthy-adult homozygote is documented.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: p.Arg408Trp activity was 1.85% of wild type, far below the VCEP BS3 requirement of greater than 85%.	vcep_ps3_functional_assay_pah PMID:17935162 PMID:18937047 PMID:18538294
BS4	Not assessed	Not assessed: no documented affected relative without the variant or other family-level non-segregation evidence.
BP1	N/A	Not applicable: the PAH VCEP explicitly marks BP1 not applicable for this framework.	cspec
BP2	N/A	Not applicable: the PAH VCEP explicitly designates BP2 as not applicable for this framework.	cspec
BP3	N/A	Not applicable: the PAH VCEP explicitly designates BP3 as Not Applicable for this framework.	cspec
BP4	Met	Met at Supporting: SpliceAI maximum delta score 0.092 is below the VCEP BP4 no-splice-impact threshold of <0.1.	cspec spliceai
BP5	Not assessed	Not assessed: no affected case with this variant and a documented alternate molecular diagnosis explaining disease is available.	cspec
BP6	N/A	Not applicable: the PAH VCEP prohibits BP6 use under this framework.	cspec
BP7	Met	Met at Supporting: BP4 is met, and the exon-12 variant is outside the first and last 3 exon bases required by the VCEP.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.