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_000277.3(PAH):c.1330C>T (p.Leu444Phe)

CA386492873

551287 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 36f8536e-265a-49f1-825f-de11b9fa12b5

Approved on: 2026-01-06

Published on: 2026-01-06

HGVS expressions

NM_000277.3:c.1330C>T

NM_000277.3(PAH):c.1330C>T (p.Leu444Phe)

NC_000012.12:g.102839204G>A

CM000674.2:g.102839204G>A

NC_000012.11:g.103232982G>A

CM000674.1:g.103232982G>A

NC_000012.10:g.101757112G>A

NG_008690.1:g.83399C>T

NG_008690.2:g.124207C>T

ENST00000553106.6:c.1330C>T

ENST00000307000.7:c.1315C>T

ENST00000551114.2:n.992C>T

ENST00000553106.5:c.1330C>T

ENST00000635528.1:n.845C>T

NM_000277.1:c.1330C>T

NM_000277.2:c.1330C>T

NM_001354304.1:c.1330C>T

NM_001354304.2:c.1330C>T

Likely Pathogenic

PM3_Strong PP4 PP3 PM2

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1330C>T (p.Leu444Phe) variant in PAH was detected in multiple patients with PKU in trans with the pathogenic variants c.441+3G>C(PMID: 28982351) and c.722G>A (PMID: 26600521). This variant was absent in population databases. Multiple lines of 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: PM3_Strong, PM2, PP3, PP4.

PM3_Strong

This variant was detected in trans with the pathogenic variants c.441+3G>C and c.722G>A (PMID: 28982351, 26600521 ). points=2

PP4

Variant was detected in 2 patients affected with PKU. Variable sites in patient genes were aligned with the corresponding sites from the respective parents. This was seen in trans with another variant listed in ClinVar. Those with BH4 cofactor deficiency were excluded PMID: 28982351, 26600521

PP3

Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (MutationTaster). REVEL=0.885

PM2

This variant is present in European (non-Finnish) populations at a frequency of 0.00006 (Gnomad). This variant is absent from the Exac population database

PM5

No other variants have been documented in ClinVar at this amino acid residue.

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.