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.1117G>A (p.Ala373Thr)

CA229351

102529 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8686a349-d7cd-48e5-8286-1fc2466ab98c

HGVS expressions

NM_000277.3:c.1117G>A

NM_000277.3(PAH):c.1117G>A (p.Ala373Thr)

NC_000012.12:g.102843728C>T

CM000674.2:g.102843728C>T

NC_000012.11:g.103237506C>T

CM000674.1:g.103237506C>T

NC_000012.10:g.101761636C>T

NG_008690.1:g.78875G>A

NG_008690.2:g.119683G>A

ENST00000553106.6:c.1117G>A

ENST00000307000.7:c.1102G>A

ENST00000549247.6:n.876G>A

ENST00000551114.2:n.779G>A

ENST00000553106.5:c.1117G>A

ENST00000635477.1:n.221G>A

ENST00000635528.1:n.632G>A

NM_000277.1:c.1117G>A

NM_000277.2:c.1117G>A

NM_001354304.1:c.1117G>A

NM_001354304.2:c.1117G>A

Likely Pathogenic

PP4_Moderate PM3 PM2

PS3 PP3 PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1117G>A (p.Ala373Thr) variant in PAH has been reported in multiple individuals with mild HPA (BH4 deficiency excluded, PP4_Moderate). This variant is absent in population databases (PM2). This variant was detected with pathogenic variants c.442-1G>A (PMID: 10484807) and in trans with p.Arg261Gln (PMID: 29316886). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3.

PP4_Moderate

detected in a patient with mild HPA (4 mg/dL). BH4 deficiency excluded by urinary pteridine HPLC and DHPR activity. PMID: 10484807

PM3

detected with IVS4-1G>A. parental analysis not reported PMID: 10484807; detected in trans with p.Arg261Gln (P, 9 submitters) PMID: 29316886

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PS3

Residual activity in prokaryotic system (56%) PMID: 16091306

Residual activity in prokaryotic system (56%); Hill coefficient 1.8; binding affinity for L-Phe of PAH mutant protein (144+/- 14) PubMed:16091306

PP3

Computational evidence is conflicting: Deleterious in SIFT, MutationTaster; Benign in PolyPhen2-HVAR, REVEL=0.739.

PM5

A373D Likely pathogenic

Approved on: 2022-06-12

Published on: 2022-06-12

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