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]

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Variant: NM_000277.1(PAH):c.466G>C (p.Ala156Pro)

CA229562

102688 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1d56d7cf-cc3f-4605-a126-3d23c461b8c7

HGVS expressions

NM_000277.1:c.466G>C

NM_000277.1(PAH):c.466G>C (p.Ala156Pro)

NC_000012.12:g.102866639C>G

CM000674.2:g.102866639C>G

NC_000012.11:g.103260417C>G

CM000674.1:g.103260417C>G

NC_000012.10:g.101784547C>G

NG_008690.1:g.55964G>C

NG_008690.2:g.96772G>C

ENST00000553106.6:c.466G>C

ENST00000307000.7:c.451G>C

ENST00000549111.5:n.562G>C

ENST00000551988.5:n.530+10823G>C

ENST00000553106.5:c.466G>C

NM_000277.2:c.466G>C

NM_001354304.1:c.466G>C

NM_000277.3:c.466G>C

NM_001354304.2:c.466G>C

NM_000277.3(PAH):c.466G>C (p.Ala156Pro)

Pathogenic

PM2_Supporting PS3_Supporting PP4_Moderate PM3_Very Strong

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.466G>C (p.Ala156Pro) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 26322415). This variant is absent in population databases. This variant was detected in trans with multiple pathogenic variants: p.H220P (PMID 26322415); c.611A>G (aka EX6-96A>G, PMID: 26600521); p.V5Sfs*33, p.R158W, p.R241C (2 patients), p.R261Q, p.R400T, p.T418P (PMID: 30050108). Functional studies show the PAH A156P mutant produces reduced protein (8.7% of wild type), with a residual enzyme activity of 10.4% (PMID 24327145). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2_supporting, PP4_Moderate, PS3_supporting.

PM2_Supporting

Absent from controls in ExAC, 1000 Genomes, and ESP

PS3_Supporting

PMID 24327145: Relative quantity of PAH proteins for A156P 8.7%, the residual enzyme activity 10.4%

PMID 24327145: Relative quantity of PAH proteins for A156P 8.7%, the residual enzyme activity 10.4% PubMed:24327145

PP4_Moderate

p.[A156P] reported in one patient with classic PKU (Phe levels >20mg/dl). All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. PMID: 26322415

PMID 19915519: phenotypes were classified based on the pretreatment plasma phenylalanine (phe) levels or the phe level at diagnosis. Accordingly, 113 patients were classic PKU (phe >1200 uM/L) (113/212); 66, mild PKU (phe 600-1200 uM/L) (66/212); 15, MHP (phe 120-600 uM/L) (15/212); 18 cases were unclassified, with their phe level unavailable. Listed in Table 2, no specific phe level specified for this patient. No comment on exclusion of BH4 deficiency. PubMed:19915519

PMID 26322415: listed p.[A156P];[H220P] in one patient with classic PKU (Phe levels >20mg/dl). All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2mg/dl. BH4 deficiency was excluded byanalysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. PubMed:26322415

PM3_Very Strong

PMID 26322415: detected with p.[H220P] (not in ClinVar, LP by PAH VCEP) All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing. Detected with c.611A>G (EX6-96A>G, P-6 submitters), parental analysis performed. PMID: 26600521 p.A156P/p.V5Sfs*33 (P-1), p.R158W (P-4)/p.A156P, p.R241C (P-8)/p.A156P (2 patients), p.R261Q (P-9)/p.A156P, p.A156P/p.R400T (P-1), p.A156P/p.T418P (P-1) The validation tests on parents were performed using Sanger sequencing. PMID: 30050108 Detected with p.R408Q parental analysis not reported PMID: 25894915

Approved on: 2023-12-30

Published on: 2023-12-30

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