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_001354304.2:c.1246C>A

CA16020980

987913 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 04c30910-babe-4e4b-a469-d820d4147268

Approved on: 2024-11-17

Published on: 2024-11-18

HGVS expressions

NM_001354304.2:c.1246C>A

NC_000012.12:g.102840469G>T

CM000674.2:g.102840469G>T

NC_000012.11:g.103234247G>T

CM000674.1:g.103234247G>T

NC_000012.10:g.101758377G>T

NG_008690.1:g.82134C>A

NG_008690.2:g.122942C>A

ENST00000553106.6:c.1246C>A

ENST00000307000.7:c.1231C>A

ENST00000551114.2:n.908C>A

ENST00000553106.5:c.1246C>A

ENST00000635477.1:c.350C>A

ENST00000635528.1:n.761C>A

NM_000277.1:c.1246C>A

NM_000277.2:c.1246C>A

NM_001354304.1:c.1246C>A

NM_000277.3:c.1246C>A

Likely Pathogenic

PP3_Strong PM3_Supporting PM5_Supporting PM2_Supporting PP4

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1246C>A (p.Pro416Thr) variant in PAH has been reported in 1 patient with mild non-PKU HPA with Phe = 246-420umol/L (BH4 deficiency not excluded) (PP4; PMID: 9380432). It has been reported in unknown phase with the pathogenic p.R408Q variant (ClinVar ID: 577) (PM3_Supporting). This variant is absent from the population database gnomAD v2.1.1. (PM2_Supporting). This variant is predicted to be deleterious by REVEL (score 0.965) (PP3_Strong). A different missense variant at the same site, p.Pro416Gln, has been classified as likely pathogenic in ClinVar by the PAH VCEP (ID: 558091, PM5_Supporting). 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_Supporting, PM3_Supporting, PP3_Strong, PP4, PM5_supporting.

PP3_Strong

Predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.965.

PM3_Supporting

PMID: 32668217: 1 case with PAH deficiency (no further specification), in unknown phase with path variant p.R408Q (ClinVar ID: 577) (0.5pts)

PM5_Supporting

c.1246A>T (p.Pro416Gln) is likely path by PAH VCEP in ClinVar (ID: 558091)

PM2_Supporting

Variant absent from population database gnomAD v4.1.0

PP4

PMID: 9380432 - P416T detected with mild non-PKU HPA, plasma Phe = 246-420umol/L on unrestricted diet, BH4 deficiency not excluded (number of patients/alleles not specified) - see Figure 1

Curation History

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