Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000277.3(PAH):c.1247C>A (p.Pro416Gln)

CA16020981

558091 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e4cbab06-2651-41ac-ae9f-526351a9e939

HGVS expressions

NM_000277.3:c.1247C>A

NM_000277.3(PAH):c.1247C>A (p.Pro416Gln)

NC_000012.12:g.102840468G>T

CM000674.2:g.102840468G>T

NC_000012.11:g.103234246G>T

CM000674.1:g.103234246G>T

NC_000012.10:g.101758376G>T

NG_008690.1:g.82135C>A

NG_008690.2:g.122943C>A

ENST00000307000.7:c.1232C>A

ENST00000553106.5:c.1247C>A

NM_000277.1:c.1247C>A

NM_000277.2:c.1247C>A

NM_001354304.1:c.1247C>A

NM_001354304.2:c.1247C>A

Likely Pathogenic

PP4 PP3 PM3 PM2

PS3 PM5 BS3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1247C>A (p.Pro416Gln) variant in PAH has been reported in 2 patients with mild PKU (PP4; PMID: 27413125, 31623983). This variant has been detected with pathogenic variants: p.I306V (PMID: 23430547) and c.664_665del (PMID: 17502162) (PM3). This variant has an extremely low frequency in gnomAD (MAF=0.000008792, PM2), and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.986 (PP3). This variant was shown to retain enzyme activity, but unfolds at a faster rate than WT (PMID: 18937047). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4.

PP4

PMID: 31623983 - P416Q detected in 1 patient with mild PKU (serum Phe 600–900 μmol/L); BH4 deficiency not excluded PMID: 27413125 - P416Q identified in 1 patient with Phe = 704umol/L, patient stated to be responsive to sapropterin dihydrochloride

PP3

Predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.986

PM3

PMID: 23430547 - P416Q detected with I306V (Pathogenic in ClinVar, VarID:618, 7 submitters); phase not confirmed - 0.5 points. PMID: 17502162 - P416Q detected with c.664_665del (p.Glu221_Asp222insTer)(Pathogenic, VarID:133249, 3 submitters) = 0.5 pts Total = 1 point

PM2

gnomAD MAF = 0.000008792 (European Non-Finnish)

PS3

BioPku database reports P416Q PAH activity = 111%; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf

PM5

c.1246A>T (p.Pro416Thr) is VUS by PAH VCEP.

BS3

other assays (e.g., reaction kinetics, protein aggregation and folding) show a deleterious effect: P416Q expressed in E. coli was shown to retain catalytic activity, a 2.2-fold increase in Kd for BH4, but unfolds at a faster rate than WT. BH4 was shown to stabilize the mutant protein in a dose-dependent manner similar to WT. PMID: 18937047

Approved on: 2021-03-12

Published on: 2021-03-12

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