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_000277.1(PAH):c.638T>C (p.Leu213Pro)

CA273109

92747 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1adb5216-c67d-4ebf-8b37-89b36d1f2625

Approved on: 2018-10-01

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.638T>C

NM_000277.1(PAH):c.638T>C (p.Leu213Pro)

NC_000012.12:g.102855204A>G

CM000674.2:g.102855204A>G

NC_000012.11:g.103248982A>G

CM000674.1:g.103248982A>G

NC_000012.10:g.101773112A>G

NG_008690.1:g.67399T>C

NG_008690.2:g.108207T>C

NM_000277.2:c.638T>C

NM_001354304.1:c.638T>C

NM_000277.3:c.638T>C

ENST00000307000.7:c.623T>C

ENST00000549111.5:n.734T>C

ENST00000553106.5:c.638T>C

Pathogenic

PP4_Moderate PM3_Very Strong PP3 PM2

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.638T>C (p.Leu213Pro) variant in PAH has been reported in in 4 patients with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8659548; PMID: 19292873; PMID: 21147011). This variant is absent from large population studies (PM2; http://exac.broadinstitute.org). This variant was detected in trans with c.1066-11G>A, E390G, D415N, R261X.(Pathogenic in ClinVar) (PM3_Very-strong; PMID: 19292873; PMID: 21147011; PMID: 8632937). Computational prediction tools and conservation analysis suggest that the c.638T>C variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong

PP4_Moderate

Found in 4 patients: (Phe levels 240 umol/L, 1936 uM, mHPA). BH4 deficiency excluded in 2 patients. Upgraded per ClinGen PAHEP PMID: 8659548; PMID: 19292873; PMID: 21147011

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). Seen on 2 alleles in 2 patients with mHPA. PubMed:21147011

We sequenced the entire gene for phenylalanine hydroxylase in 51 unrelated hyperphenylalaninemia patients from Southern Italy. Patient 42 had L213P variant with c.1066-11G>A, pretreatment Phe level was 1936 uM, HPA I phenotype PubMed:19292873

One hundred forty-nine patients en- rolled in the Maternal PKU Collaborative Study were subjects for clinical and molecular investigations. PAH gene mutations associated with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 of 294 independent mutant chromosomes. Patient 1/1101/ENO-10, 2nd mutation not found, Phe level=240 umol/L, MHP, English/Mexican ethnicity. PubMed:8659548

PM3_Very Strong

Detected in trans with c.1066-11G, E390G, D415N, R261X. P/LP in ClinVar PMID: 19292873; PMID: 21147011; PMID: 8632937

PAH Genotype: L213P/R261X (VarID 610, Pathogenic) PubMed:8632937

Detected in 2 patients: p.L213P/p.E390G (VarID 625 P/LP) and p.L213P/p.D415N (VarID 617, Pathogenic). PubMed:21147011

L213P in trans with c.1066-11G>A ((Pathogenic in ClinVar, VarID 607) PubMed:19292873

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster

PM2

Not found in ExAC, gnomAD, 1000G, or ESP

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