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.1205T>G

CA16020970

987755 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 66e02e7e-b8c3-4033-828b-04cc081ba5c4

Approved on: 2024-11-17

Published on: 2024-11-18

HGVS expressions

NM_001354304.2:c.1205T>G

NC_000012.12:g.102840510A>C

CM000674.2:g.102840510A>C

NC_000012.11:g.103234288A>C

CM000674.1:g.103234288A>C

NC_000012.10:g.101758418A>C

NG_008690.1:g.82093T>G

NG_008690.2:g.122901T>G

ENST00000553106.6:c.1205T>G

ENST00000307000.7:c.1190T>G

ENST00000551114.2:n.867T>G

ENST00000553106.5:c.1205T>G

ENST00000635477.1:c.309T>G

ENST00000635528.1:n.720T>G

NM_000277.1:c.1205T>G

NM_000277.2:c.1205T>G

NM_001354304.1:c.1205T>G

NM_000277.3:c.1205T>G

Likely Pathogenic

PP4_Moderate PP3_Strong PM2_Supporting

PM5

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.1205 (p.Phe402Cys) variant in PAH has been detected in 1 Japanese patient with mild HPA and BH4 deficiency excluded (PMID: 21307867; PP4_Moderate). This variant is absent from population databases (PM2_Supporting), and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.94 (PP3_Strong). 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, PP3_Strong, PP4.

PP4_Moderate

PMID: 21307867 - F402C detected in 1 Japanese patient with mild HPA, serum Phe = 180-600umol/l. BH4 deficiency was excluded by analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine.

PP3_Strong

Predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.94 (>0.932)

PM2_Supporting

Variant absent from gnomAD v4.1.0

PM5

At same codon as c.1204T>A (p.F402I), c.1204T>C (p.F402L), and c.1204T>G (p.F402V) - all curated as VUS by ClinGen PAH VCEP.

Curation History

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