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]

Link to SEPIO compliant JSON-LD document

CA16020927

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a75df102-4c40-499b-a404-588978f4762e

HGVS expressions

NM_000277.1:c.1066-7C>A

NC_000012.12:g.102843786G>T

CM000674.2:g.102843786G>T

NC_000012.11:g.103237564G>T

CM000674.1:g.103237564G>T

NC_000012.10:g.101761694G>T

NG_008690.1:g.78817C>A

NG_008690.2:g.119625C>A

ENST00000553106.6:c.1066-7C>A

ENST00000307000.7:c.1051-7C>A

ENST00000549247.6:n.825-7C>A

ENST00000551114.2:n.728-7C>A

ENST00000553106.5:c.1066-7C>A

ENST00000635477.1:n.170-7C>A

ENST00000635528.1:n.581-7C>A

NM_000277.2:c.1066-7C>A

NM_001354304.1:c.1066-7C>A

NM_000277.3:c.1066-7C>A

NM_001354304.2:c.1066-7C>A

Likely Pathogenic

PP4_Moderate PM2 PM3

PP3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1066-7C>A variant in PAH has been reported in 3 individuals with PAH deficiency (BH4 deficiency excluded, PMID: 12655553, 21147011, 21307867). This variant has extremely low frequency in gnomAD (MAF=0.00001). This variant was detected in the homozygous state, with maternity and paternity confirmed (PMID: 12655553); and with pathogenic variant IVS11-2A>G (PMID: 21147011). 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

IVS10-7C>A identified in 3 PKU patients. One had BH4 deficiency excluded by assessment of PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 12655553, PMID: 21147011, PMID: 21307867

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). IVS10-7C>A seen on 1 allele. PubMed:21147011

we studied the genotypic spectrum of 39 Turkish families with PAH deficiency. Twenty-three mutations were identified including a novel mutation: IVS10-7C>A (c.1066-7C>A) in Intron 10 on 2 alleles. PubMed:12655553

PM2

Absent from ExAC, 1000G, ESP. Extremely low frequency in gnomAD (MAF=0.00001)

PM3

c.1066-7C>A homozygous, with maternity and paternity confirmed PMID: 12655553; detected with IVS11-2A>G (P 1 submiiter), parental analysis not performed/reported PMID: 21147011 1.0 pts

PP3

HSF: Broken WT Acceptor Site; Splice AI Benign (0.12); TraP 0.266 (possibly damaging, >95%ile)

Approved on: 2020-08-10

Published on: 2021-09-26

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