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

Variant: NM_000277.1(PAH):c.1039C>T (p.Leu347Phe)

CA229296

102488 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ff17bdce-39eb-49fe-bc18-7aab80634091

HGVS expressions

NM_000277.1:c.1039C>T

NM_000277.1(PAH):c.1039C>T (p.Leu347Phe)

NC_000012.12:g.102844362G>A

CM000674.2:g.102844362G>A

NC_000012.11:g.103238140G>A

CM000674.1:g.103238140G>A

NC_000012.10:g.101762270G>A

NG_008690.1:g.78241C>T

NG_008690.2:g.119049C>T

ENST00000553106.6:c.1039C>T

ENST00000307000.7:c.1024C>T

ENST00000549247.6:n.798C>T

ENST00000551114.2:n.701C>T

ENST00000553106.5:c.1039C>T

ENST00000635477.1:n.143C>T

ENST00000635528.1:n.554C>T

NM_000277.2:c.1039C>T

NM_001354304.1:c.1039C>T

NM_000277.3:c.1039C>T

NM_001354304.2:c.1039C>T

Uncertain Significance

PP3 PP4_Moderate PM2

PM3 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.1039C>T (p.Leu347Phe) variant in PAH has been reported twice in patients with PAH deficiency (BH4 deficiency excluded, PMID: 8659548, 21147011). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3.

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster, REVEL=0.951

PP4_Moderate

L347F found in 2 hyperphenylalaninemic patients. BH4 deficiency excluded in 1 patient Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 8659548, PMID: 21147011

149 hyperphenylalaninemic females. L347F seen on 1 allele. PubMed:8659548

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). L347F found in homozygous state in 1 patient. PubMed:21147011

PM2

Absent from ExAC, gnomAD, ESP, 1000G

PM3

L347F found in homozygous state in 1 patient. parental analysis not reported

L347F found in homozygous state in 1 patient. PubMed:21147011

PM5

Only variant in codon

Approved on: 2020-08-13

Published on: 2021-07-09

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