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.117C>G (p.Phe39Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA251537

605 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3e20a694-2d0a-4342-b7b4-eeea90dbee7d

Approved on: 2020-03-27

Published on: 2021-06-09

HGVS expressions

NM_000277.3:c.117C>G

NM_000277.3(PAH):c.117C>G (p.Phe39Leu)

ENST00000553106.6:c.117C>G

ENST00000307000.7:c.102C>G

ENST00000546844.1:c.117C>G

ENST00000548677.2:n.204C>G

ENST00000548928.1:n.39C>G

ENST00000549111.5:n.213C>G

ENST00000550978.6:n.101C>G

ENST00000551337.5:c.117C>G

ENST00000551988.5:n.206C>G

ENST00000553106.5:c.117C>G

ENST00000635500.1:n.85C>G

NM_000277.1:c.117C>G

NM_000277.2:c.117C>G

NM_001354304.1:c.117C>G

NM_001354304.2:c.117C>G

NC_000012.12:g.102912842G>C

CM000674.2:g.102912842G>C

NC_000012.11:g.103306620G>C

CM000674.1:g.103306620G>C

NC_000012.10:g.101830750G>C

NG_008690.1:g.9761C>G

NG_008690.2:g.50569C>G

Pathogenic

PM3_Very Strong PP1 PP4 PM2

PS3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.117C>G (p.Phe39Leu) variant in PAH has been reported in multiple individuals with PKU. (PMID: 23430918, 8659548, 8406445, 2063869). This variant has an extremely low allele frequency in ExAC, gnomAD, 1000 Genomes, ESP (MAF=0.00016). This variant was detected with multiple pathogenic variants: T81P, V177L (PMID: 8659548), F55fsdelT (2 patients, PMID: 15557004), p.I65T, p.R408W (4 patients), p.R252W, p.E280K, c.1066-11G>A, c.1315+1G>A (PMID: 23430918). There is cosegregation with disease in affected siblings in 2 families PMID: 2063869, 8592329). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4, PP1.

PM3_Very Strong

detected in trans with p.Ser349Arg PMID: 2063869 (P, OMIM). Detected with T81P (P, 1 submitter), V177L (P-3/LP-1) PMID: 8659548 R48W, F55fsdelT (2 patients, P-5) PMID: 15557004 p.I65T (P-10); p.R408W (4 patients, P-14); p.R252W (P-7); p.E280K (P-9); c.1066-11G>A (P-7); c.1315+1G>A (P-13) PMID: 23430918 parental analysis not reported

PP1

Cosegregation with disease in 2 siblings in each of 2 families PMID: 2063869, PMID: 8592329

PP4

Detected in multiple affected individuals: PMID: 23430918, PMID: 8659548, PMID: 8406445, PMID: 2063869

PM2

Extremely low frequency if recessive in ExAC, gnomAD, 1000 Genomes, ESP (MAF=0.00016)

PS3

p.F39L had PAH activity of: 73% (COS cells); 67% (e. coli); 47% (TNT-T7); and 46% (HEK293)

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.