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

CA229426

102585 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

PM3_Strong PP3 PP4_Moderate PM2

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.

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

PP3

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

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

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

Approved on: 2020-08-17

Published on: 2021-12-12

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