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_000277.1:c.1243G>T

CA16020978

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: e80bed8c-0fdd-40df-a155-3f2773450203

Approved on: 2021-10-10

Published on: 2021-10-10

HGVS expressions

NM_000277.1:c.1243G>T

ENST00000553106.6:c.1243G>T

ENST00000307000.7:c.1228G>T

ENST00000551114.2:n.905G>T

ENST00000553106.5:c.1243G>T

ENST00000635477.1:n.347G>T

ENST00000635528.1:n.758G>T

NM_000277.2:c.1243G>T

NM_001354304.1:c.1243G>T

NM_000277.3:c.1243G>T

NM_001354304.2:c.1243G>T

NC_000012.12:g.102840472C>A

CM000674.2:g.102840472C>A

NC_000012.11:g.103234250C>A

CM000674.1:g.103234250C>A

NC_000012.10:g.101758380C>A

NG_008690.1:g.82131G>T

NG_008690.2:g.122939G>T

Pathogenic

PP4_Moderate PP3 PM3_Strong PM2 PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1243G>T (p.Asp415Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21462123, 26503515). This variant is absent in population databases. This variant was detected in trans with pathogenic variants: p.Val399= (PMID: 28982351); and p.Ala345Thr (LP by PAH VCEP, PMID: 30050108). Computational evidence support a deleterious effect. Another missense change at the same amino acid (p.Asp415Asn) is interpreted as pathogenic by multiple submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_Strong, PM5, PP3.

PP4_Moderate

D415Y found in 1 PKU patient. BH4 deficiency was assessed with dihydropteridine reductase activity, urinary biopterin and neopterin ratio. PMID: 21462123, 26503515

A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. 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. D415Y was found on 1 allele PubMed:26503515

Mutations of the PAH gene were detected in exons 1-13 with flanking introns of PAH gene by PCR and DNA sequencing in 47 families with PKU. D415Y has not been reported previously. PubMed:21462123

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster, REVEL=0.923

PM3_Strong

detected in trans with p.Val399= (P 5 submitters) variable sites in patient genes were aligned with the corresponding sites from the respective parents. PMID: 28982351 and p.A345T (LP by PAH VCEP/ US by 1 submitter) validation tests on parents were performed using Sanger sequencing PMID: 30050108 2.0 points

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM5

c.1243G>A (p.Asp415Asn) Pathogenic 9 submitters (PAH VCEP) and LP 2 submitters

Curation History

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