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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.2(PAH):c.997C>T (p.Leu333Phe)

CA114366

624 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: dfc4fff9-3ef3-4b41-ac3a-94f9f8b7aa2d

Approved on: 2022-03-13

Published on: 2022-04-16

HGVS expressions

NM_000277.2:c.997C>T

NM_000277.2(PAH):c.997C>T (p.Leu333Phe)

NC_000012.12:g.102844404G>A

CM000674.2:g.102844404G>A

NC_000012.11:g.103238182G>A

CM000674.1:g.103238182G>A

NC_000012.10:g.101762312G>A

NG_008690.1:g.78199C>T

NG_008690.2:g.119007C>T

ENST00000553106.6:c.997C>T

ENST00000307000.7:c.982C>T

ENST00000549247.6:n.756C>T

ENST00000551114.2:n.659C>T

ENST00000553106.5:c.997C>T

ENST00000635477.1:n.101C>T

ENST00000635528.1:n.512C>T

NM_000277.1:c.997C>T

NM_001354304.1:c.997C>T

NM_000277.3:c.997C>T

NM_001354304.2:c.997C>T

NM_000277.3(PAH):c.997C>T (p.Leu333Phe)

Pathogenic

PP4_Moderate PS3_Supporting PP3 PM2 PM3_Strong

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.997C>T (p.Leu333Phe) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). It was detected with multiple pathogenic variants: p.E390G (PMID: 8098245); p.R261Q (PMID: 21147011); p.S110L (LP by PAH VCEP, PMID: 26542770). This variant is absent in population databases. In an eukaryotic expression system, the L333F mutant had 7% PAH activity as compared to wild type (PMID: 10479481). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3, PS3_supporting.

PP4_Moderate

Seen in 1 patient with hyperphe. Cofactor deficiency ruled out: a needle biopsy of the liver, performed to rule out a cofactor deficiency, showed a PAH activity of 10% of the control (6 micromoles of tyr/h/g of protein). Dihydropteridine reductase activity was normal (90 nanomoles/min/mg of protein). PMID: 8098245

PS3_Supporting

In an eukaryotic expression system, L333F mutant had 7% PAH activity as compared to wt. PMID: 10479481. This is consistent with in vivo measurement: A needle biopsy of the liver showed a PAH activity of 10% of the control (6 micromoles of tyr/h/g of protein). Genotype was L333F/E390G. PMID: 8098245

PP3

Predicted deleterious in SIFT, Polyphen2, LRT, FATHMM, PROVEAN

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM3_Strong

L333F seen with E390G (Pathogenic/Likely Pathogenic), parental analysis not reported PMID: 8098245; Homozygous (PMID: 20920871); p.R261Q (P), parental analysis not routinely performed (PMID: 21147011); in trans with c.329C>T, p.S110L (LP by PAH VCEP, PMID: 26542770) 2.0 points

PM5

No other variant in this codon in ClinVar

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.