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_000277.1(PAH):c.1159T>C (p.Tyr387His)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229363

102539 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 29f8cc29-9bc1-4b4f-aeb2-832664291950

Approved on: 2020-08-17

Published on: 2021-11-21

HGVS expressions

NM_000277.1:c.1159T>C

NM_000277.1(PAH):c.1159T>C (p.Tyr387His)

NC_000012.12:g.102843686A>G

CM000674.2:g.102843686A>G

NC_000012.11:g.103237464A>G

CM000674.1:g.103237464A>G

NC_000012.10:g.101761594A>G

NG_008690.1:g.78917T>C

NG_008690.2:g.119725T>C

ENST00000553106.6:c.1159T>C

ENST00000307000.7:c.1144T>C

ENST00000549247.6:n.918T>C

ENST00000551114.2:n.821T>C

ENST00000553106.5:c.1159T>C

ENST00000635477.1:n.263T>C

ENST00000635528.1:n.674T>C

NM_000277.2:c.1159T>C

NM_001354304.1:c.1159T>C

NM_000277.3:c.1159T>C

NM_001354304.2:c.1159T>C

NM_000277.3(PAH):c.1159T>C (p.Tyr387His)

Likely Pathogenic

PP4_Moderate PM2 PP3 PM3_Strong

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1159T>C (p.Tyr387His) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21147011, 21890392). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.L48S, p.Y204X (PMID: 21147011); p.T323del (PMID: 9169088); c.754C>T, p.Arg252Trp (PMID: 21890392); p.Ala395Pro (PMID: 23357515); p.R261Q, c.782G>A (PMID: 23690520). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.

PP4_Moderate

Y387H seen in 3 hyperphenylalaninemic patients. BH4 deficiency excluded by assessment of PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 21147011, PMID: 21890392

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster, REVEL 0.94

PM3_Strong

Y387H detected with L48S and Y204X. Both pathogenic in ClinVar. Parental analysis not performed. PMID: 21147011; delT323, p 2 submitters parental analysis not reported PMID: 9169088; c.754C>T, p.Arg252Trp (maternal) P 7 submitters PMID: 21890392; p.[Tyr387His]; [Ala395Pro] parental analysis not reported P 2 submitters PMID: 23357515; p.R261Q c.782G>A P 11 submitters parental studies not reported PMID: 23690520 3.5 pts

PM5

Only missense variant found at this codon in ClinVar

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.