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]

Variant: NM_000277.3(PAH):c.1252A>C (p.Thr418Pro)

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CA229418

102580 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8328fe09-187d-4840-9cd3-5e9160964b68

Approved on: 2020-06-08

Published on: 2021-06-09

HGVS expressions

NM_000277.3:c.1252A>C

NM_000277.3(PAH):c.1252A>C (p.Thr418Pro)

ENST00000553106.6:c.1252A>C

ENST00000307000.7:c.1237A>C

ENST00000551114.2:n.914A>C

ENST00000553106.5:c.1252A>C

ENST00000635477.1:n.356A>C

ENST00000635528.1:n.767A>C

NM_000277.1:c.1252A>C

NM_000277.2:c.1252A>C

NM_001354304.1:c.1252A>C

NM_001354304.2:c.1252A>C

NC_000012.12:g.102840463T>G

CM000674.2:g.102840463T>G

NC_000012.11:g.103234241T>G

CM000674.1:g.103234241T>G

NC_000012.10:g.101758371T>G

NG_008690.1:g.82140A>C

NG_008690.2:g.122948A>C

Pathogenic

PM3_Very Strong PP4_Moderate PP3 PM2

BS3 PS3

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1252A>C (p.Thr418Pro) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PMID: 26503515). This variant has an extremely low allele frequency (MAF=0.00003) in gnomAD. It was detected in trans with multiple pathogenic variants: p.Arg243Gln, p.Arg408Gln, p.Arg176*, EX6-96A＞G, p.Tyr356*, p.Arg111* (PMID: 28982351). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3.

PM3_Very Strong

p.Arg243Gln (P 11 submitters), p.Arg408Gln (P 7 submitters), p.Arg176* (P 9 submitters), EX6-96A＞G (P 6 submitters), p.Tyr356*(P), p.Arg111* (P 6 submitters); variable sites in patient genes were aligned with the corresponding sites from the respective parents. PMID: 28982351

PP4_Moderate

Seen in multiple individuals with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PMID: 26503515

Seen in a patient with Classic PKU (Phe < 1200 lmol/L)) in trans with EX6-96A>G PubMed:16256386

Seen in multiple individuals with PKU, these patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PubMed:26503515

PP3

Multiple lines of evidence (MutationTaster, SIFT, Polyphen) support deleterious effect.

PM2

absent in 1000G and Exac. MAF=0.00003 in gnomAD.

BS3

In vivo studies show a 105 and 106 % PAH enzymatic activity.

In vivo studies show a 105 and 106 % PAH enzymatic activity. Site-directed mutagenesis and in vitro expression analysis were performed as previously described (Svensson et al., 1992). Immunoreactivity 79,95 % wt. RNA level 105, ND. cos cells transfected with PAH cDNA. PubMed:8019568

PS3

In vivo studies show a 105 and 106 % PAH enzymatic activity.

Curation History

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