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_000277.1(PAH):c.1289T>C (p.Leu430Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229426

102585 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4f473c18-c77e-4640-a9b2-3cfa3f248926

Approved on: 2020-08-17

Published on: 2021-12-12

HGVS expressions

NM_000277.1:c.1289T>C

NM_000277.1(PAH):c.1289T>C (p.Leu430Pro)

NC_000012.12:g.102840426A>G

CM000674.2:g.102840426A>G

NC_000012.11:g.103234204A>G

CM000674.1:g.103234204A>G

NC_000012.10:g.101758334A>G

NG_008690.1:g.82177T>C

NG_008690.2:g.122985T>C

ENST00000553106.6:c.1289T>C

ENST00000307000.7:c.1274T>C

ENST00000551114.2:n.951T>C

ENST00000553106.5:c.1289T>C

ENST00000635477.1:n.393T>C

ENST00000635528.1:n.804T>C

NM_000277.2:c.1289T>C

NM_001354304.1:c.1289T>C

NM_000277.3:c.1289T>C

NM_001354304.2:c.1289T>C

NM_000277.3(PAH):c.1289T>C (p.Leu430Pro)

Likely Pathogenic

PP4_Moderate PM2 PP3 PM3_Strong

PS3 PM5

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1289T>C (p.Leu430Pro) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21307867). This variant is absent in population databases. This variant was detected with pathogenic variants: p.R241C (PMID: 21147011); p.S70del, p.R241C (PMID: 30050108); c.728G>A, p.R243Q (PMID: 31355225). 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: PP4_Moderate, PM2, PM3_strong, PP3.

PP4_Moderate

L430P was found in 1 patient with PAH deficiency. BH4 deficiency excluded by analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine. PMID: 21307867

This study enrolled 203 Japanese residents with a serum phenylalanine level higher than 0.18 mm. PAH deficiency was diagnosed on the basis of absence of neurologic deterioration on a low phenylalanine diet, analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine. L430P was found on 1 allele. PubMed:21307867

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster, REVEL=0.976

PM3_Strong

L430P found with pathogenic variants (R241C, A300S). parental analysis not performed PMID: 21147011; p.L430P/p.Y414* (not in ClinVar); p.L430P/p.S70del (P 3 submitters); p.R241C/p.L430P. Validation tests on parents performed. PMID: 30050108; p.Ile324Asn, (not in ClinVar) variable sites in patient genes were aligned with the corresponding sites from the respective parents. PMID: 29316886; c.728G > A, p.R243Q (P 11 submitters). Parents were also investigated to confirm their carrier status. PMID: 31355225 3.5 pts

L430P found in trans with A300S (VarID 92751, Pathogenic in ClinVar) in 1 PKU patient, and R241C (VarID 102803, Pathogenic in ClinVar) in 1 PKU patient. PubMed:21147011

PS3

Using the phenylalanine breath test, cumulative recovery rate (CRR) for a classical PKU patient (R413P/L430P) is close to 0 vs. ~10-15 for carriers or controls.

We performed the phenylalanine breath test as reliable method to determine BH4 responsiveness. Phenylalanine breath test quantitatively measures the conversion of L-[1-13C] phenylalanine to 13CO2. 20 Japanese patients with HPA were examined with a dose of 10 mg/kg of 13C-phenylalanine with or without a dose of 10 mg . kg(-1) . d(-1) of BH4 for 3 d. Figure 3 shows the phenylalanine breath test [cumulative recovery rate (CRR)] for a classical PKU patient (R413P/L430P) is close to 0 vs. ~10-15 for carriers or controls. PubMed:15319459

PM5

Only variant found in this codon in ClinVar

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.