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_000277.2(PAH):c.500A>T (p.Asn167Ile)

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CA220584

92743 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a49cb655-9cb0-4fac-959d-26d4290227d6

Approved on: 2018-08-28

Published on: 2019-04-06

HGVS expressions

NM_000277.2:c.500A>T

NM_000277.2(PAH):c.500A>T (p.Asn167Ile)

NC_000012.12:g.102866605T>A

CM000674.2:g.102866605T>A

NC_000012.11:g.103260383T>A

CM000674.1:g.103260383T>A

NC_000012.10:g.101784513T>A

NG_008690.1:g.55998A>T

NG_008690.2:g.96806A>T

NM_000277.1:c.500A>T

NM_001354304.1:c.500A>T

NM_000277.3:c.500A>T

ENST00000307000.7:c.485A>T

ENST00000549111.5:n.596A>T

ENST00000551988.5:n.530+10857A>T

ENST00000553106.5:c.500A>T

Likely Pathogenic

PP4_Moderate PM2 PM3_Strong

PP3

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (MAF=0.00003). Absent from gnomAD, 1000G, ESP; PP4_Moderate: Found in a French patient with HPA and 2 unrelated UK patients. BH4 deficiencies not assessed/reported. Seen in 1 German patient, Cofactor deficiency was excluded by the BH4 test. 1 Spanish patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. (PMID:26666653; PMID:9012412; PMID:10679941); PM3_Strong: Patient 664 with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants. (PMID:24368688; PMID:26666653). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong).

PP4_Moderate

Found in a French patient with HPA and 2 unrelated UK patients. BH4 deficiencies not assessed/reported. Seen in 1 German patient, Cofactor deficiency was excluded by the BH4 test. 1 Spanish patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity.

PKU patients from four centers in three countries of Great Britain were studied. N167I was found in 2 unrelated patients. PubMed:9012412

A total of 302 PKU or HPA patients in 290 families were analyzed. Cofactor deficiency was excluded by the BH4 test. N167I seen in 1 patient. PubMed:10679941

364 hyperphenylalaninemic patients from 20 French Centers for Inborn Errors of Metabolism. p.Asn167Ile was found in compound heterozygous patient carrying a second null mutation. PubMed:26666653

PM2

Extremely low frequency in ExAC (MAF=0.00003). Absent from gnomAD, 1000G, ESP

PM3_Strong

Patient 664 with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants.

Patient 7: N167I/R408W PubMed:24368688

Genotype: c. [500A > T] (p.Asn167Ile); [1066-11G > A]. PubMed:26666653

PP3

Conflicting predictions of pathogenicity: Damaging in SIFT, MutationTaster, Benign in Polyphen, REVEL=0.645.

Curation History

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