Variant: NM_000277.1(PAH):c.1039C>T (p.Leu347Phe)

CA229296

102488 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: ff17bdce-39eb-49fe-bc18-7aab80634091

Approved on: 2024-11-17

Published on: 2024-11-18

HGVS expressions

NM_000277.1:c.1039C>T
NM_000277.1(PAH):c.1039C>T (p.Leu347Phe)
NC_000012.12:g.102844362G>A
CM000674.2:g.102844362G>A
NC_000012.11:g.103238140G>A
CM000674.1:g.103238140G>A
NC_000012.10:g.101762270G>A
NG_008690.1:g.78241C>T
NG_008690.2:g.119049C>T
ENST00000553106.6:c.1039C>T
ENST00000307000.7:c.1024C>T
ENST00000549247.6:n.798C>T
ENST00000551114.2:n.701C>T
ENST00000553106.5:c.1039C>T
ENST00000635477.1:c.143C>T
ENST00000635528.1:n.554C>T
NM_000277.2:c.1039C>T
NM_001354304.1:c.1039C>T
NM_000277.3:c.1039C>T
NM_001354304.2:c.1039C>T

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP3_Strong PP4_Moderate PM3_Supporting

• Not Met criteria codes: BP4 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.1039C>T (p.Leu347Phe) variant in PAH has been reported twice in patients with PAH deficiency with BH4 deficiency excluded (PMID: 8659548, 21147011) (PP4_Moderate). One of these individuals was homozygous for the variant (PMID: 21147011) (PM3_Supporting). This variant is absent in population databases (PM2_Supporting). Multiple lines of computational evidence support a deleterious effect, including REVEL score 0.951 (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, PP4_Moderate, PM3_Supporting, PP3_Strong.

Met criteria codes

• PM2_Supporting: Absent from gnomAD v4.1.0
• PP3_Strong: Predicted deleterious in SIFT, Polyphen2, MutationTaster, REVEL=0.951
• PP4_Moderate: L347F found in 2 hyperphenylalaninemic patients. BH4 deficiency excluded in 1 patient Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 8659548, PMID: 21147011
• PM3_Supporting: PMID: 21147011: L347F found in homozygous state in 1 patient. parental analysis not reported (0.5pts)

Not Met criteria codes

• BP4: Predicted deleterious in SIFT, Polyphen2, MutationTaster
• PM5: Only variant in codon