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_000277.3(PAH):c.117C>G (p.Phe39Leu)

CA251537

605 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

PM2 PM3_Very Strong PP1 PP4

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.

PM2

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

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

PS3

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

Approved on: 2020-03-27

Published on: 2021-06-09

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