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(PAH):c.1243G>A (p.Asp415Asn)

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Curation History
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CA114364

617 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d8d2e477-0bfe-4136-9489-617a94f7fda6

Approved on: 2018-08-12

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.1243G>A

NM_000277.1(PAH):c.1243G>A (p.Asp415Asn)

NC_000012.12:g.102840472C>T

CM000674.2:g.102840472C>T

NC_000012.11:g.103234250C>T

CM000674.1:g.103234250C>T

NC_000012.10:g.101758380C>T

NG_008690.1:g.82131G>A

NG_008690.2:g.122939G>A

NM_000277.2:c.1243G>A

NM_001354304.1:c.1243G>A

NM_000277.3:c.1243G>A

ENST00000307000.7:c.1228G>A

ENST00000551114.2:n.905G>A

ENST00000553106.5:c.1243G>A

ENST00000635477.1:n.347G>A

ENST00000635528.1:n.758G>A

Pathogenic

PP4_Moderate PM3_Very Strong PM2

PS3 PP3 PM5

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1243G>A (p.Asp415Asn) variant in PAH has been reported in 3 patients with Hyperphenylalaninemia (BH4 deficiency excluded). (PP4_Moderate; PMID: 1358789). This variant has an extremely low allele frequency (0.0001097 in gnomAD) (PM2; http://gnomad.broadinstitute.org). This variant was detected in trans with R408W, F39L, Y414C, IVS10-11G>A (Pathogenic in ClinVar) (PM3_Very-strong; PMID: 1358789; PMID: 12501224; PMID: 18299955). 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

D415N was found in 3 patients with HPA. Pterines and dihydropteridine reductase activity was assessed. Upgraded per ClinGen PAH EP PMID: 1358789

Haplotype analysis at the PAH locus was performed in 17 Danish families with non-PKU HPA, revealing compound heterozygosity in all individuals. Three children had inherited a G-to-A transition at codon 415 in exon 12 of the PAH gene, resulting in the substitution of asparagine for aspartate. Pterines in the urine were determined by HPLC, and dihydropteridine reductase activity in cultured fibroblasts. PubMed:1358789

PM3_Very Strong

D415N detected in trans with R408W, F39L, Y414C, IVS10-11G>A (all Pathogenic) PMID: 1358789; PMID: 12501224; PMID: 18299955

D415N was found in trans with R408W (VarID 577, Pathogenic) in 1 HPA patient. PubMed:1358789

Patient genotype: IVS10 - 11G>A (VarID607, Pathogenic) + D415N PubMed:18299955

Patient 4: F39L (VarID 605, Pathogenic)/D415N; Patient 5:Y414C (VarID 593, Pathogenic)/D415N. PubMed:12501224

PM2

Extremely low frequency in ExAC and GnomAD (MAF=0.00036) and absent from 1000G and ESP

PS3

Conflicting evidence of 2 in vitro expression: 100-128% activity of wt in mammalian system and 72+/-19% in e. coli

We have used two heterologous in vitro expression systems (a mammalian cell-free transcription-translation system and the pET system of Escherichia coli) to examine 34 mutations that have been associated with PAH deficiency in the Danish population. D415N had PAH enzyme activity of 128/100% of wt in the pcDNA3/IVT system and 72+/-19 in the pET/E. coli system. PubMed:11161839

PP3

Conflicting predictions of pathogenicity: benign in SIFT/Polyphen, damaging in FATHMM

PM5

Only variant in this codon in ClinVar

Curation History

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