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.982A>G (p.Thr328Ala)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229891

102923 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4081a5c6-1ea3-43ec-a823-3fd1e45d656c

Approved on: 2020-09-25

Published on: 2022-02-20

HGVS expressions

NM_000277.1:c.982A>G

NM_000277.1(PAH):c.982A>G (p.Thr328Ala)

NC_000012.12:g.102844419T>C

CM000674.2:g.102844419T>C

NC_000012.11:g.103238197T>C

CM000674.1:g.103238197T>C

NC_000012.10:g.101762327T>C

NG_008690.1:g.78184A>G

NG_008690.2:g.118992A>G

ENST00000553106.6:c.982A>G

ENST00000307000.7:c.967A>G

ENST00000549247.6:n.741A>G

ENST00000551114.2:n.644A>G

ENST00000553106.5:c.982A>G

ENST00000635477.1:n.86A>G

ENST00000635528.1:n.497A>G

NM_000277.2:c.982A>G

NM_001354304.1:c.982A>G

NM_000277.3:c.982A>G

NM_001354304.2:c.982A>G

NM_000277.3(PAH):c.982A>G (p.Thr328Ala)

Likely Pathogenic

PM3_Supporting PP3 PM2 PP4_Moderate

PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.982A>G (p.Thr328Ala) variant in PAH has been reported in 1 individual with PKU (BH4 deficiency excluded), detected with pathogenic variant p.L48S (PMID: 21147011). This variant has extremely low frequency in ExAC and gnomAD (MAF=0.00003). Computational evidence supports 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_supporting, PP3.

PM3_Supporting

Seen with L48S in 1 PKU patient. Parental analysis not performed. PMID: 21147011 0.5 pts

T328A seen in trans in 1 PKU patient with L48S (VarID 608, Pathogenic). PubMed:21147011

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. (REVEL=0.971)

PM2

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

PP4_Moderate

T328A seen in 1 PKU patient. BH4 deficiency was ruled out by assessment of PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 21147011

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). Seen on 1 allele. PubMed:21147011

PM5

VarID 281073, T328I, Uncertain significance

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.