Variant: NM_001354304.2:c.552G>T

CA386296891

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 548e6598-ad7f-4357-a750-d6bf46a368bb

Approved on: 2024-11-17

Published on: 2024-11-17

HGVS expressions

NM_001354304.2:c.552G>T
NC_000012.12:g.102855290C>A
CM000674.2:g.102855290C>A
NC_000012.11:g.103249068C>A
CM000674.1:g.103249068C>A
NC_000012.10:g.101773198C>A
NG_008690.1:g.67313G>T
NG_008690.2:g.108121G>T
ENST00000553106.6:c.552G>T
ENST00000307000.7:c.537G>T
ENST00000549111.5:n.648G>T
ENST00000551988.5:n.573G>T
ENST00000553106.5:c.552G>T
NM_000277.1:c.552G>T
NM_000277.2:c.552G>T
NM_001354304.1:c.552G>T
NM_000277.3:c.552G>T

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP3_Moderate PP4_Moderate PM3_Supporting

• Not Met criteria codes: PM5

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

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.552G>T (p.Lys184Asn) variant in PAH is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 184. It has been detected in a patient with phenylketonuria with pathogenic variant c.442-1G>A, phase unconfirmed (PMID: 25456745). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect (REVEL= 0.827). In summary, this variant is classified as likely pathogenic due to insufficient evidence based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2_supporting, PM3_supporting, PP3_moderate, PP4_moderate.

Met criteria codes

• PM2_Supporting: Absent from controls in gnomAD v4.1.0
• PP3_Moderate: Predicted tolerated in SIFT, possibly damaging in PolyPhen-2, and disease causing in MutationTaster. REVEL= 0.827
• PP4_Moderate: Detected in patient with Phenylketonuria with blood Phe levels >120 μmol/L. PAH, PTS, QDPR, GCH1, and PCBD1 were sequenced.
• PM3_Supporting: Detected with c.442-1G>A p.?/IVS4-1G>A which was classified as pathogenic in ClinVar. Phase unconfirmed.

Not Met criteria codes

• PM5: No other missense change at an amnio acid residue detected in ClinVar