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_000277.2(PAH):c.440C>T (p.Pro147Leu)

CA229543

102670 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: febc80a4-e7d3-4341-8bd4-c26225613b2d

HGVS expressions

NM_000277.2:c.440C>T

NM_000277.2(PAH):c.440C>T (p.Pro147Leu)

NC_000012.12:g.102877463G>A

CM000674.2:g.102877463G>A

NC_000012.11:g.103271241G>A

CM000674.1:g.103271241G>A

NC_000012.10:g.101795371G>A

NG_008690.1:g.45140C>T

NG_008690.2:g.85948C>T

NM_000277.1:c.440C>T

NM_001354304.1:c.440C>T

NM_000277.3:c.440C>T

ENST00000307000.7:c.425C>T

ENST00000549111.5:n.536C>T

ENST00000550978.6:n.424C>T

ENST00000551988.5:n.529C>T

ENST00000553106.5:c.440C>T

Likely Pathogenic

PM3_Strong PP3 PP4_Moderate PM2

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.440C>T (p.Pro147Leu) variant in PAH has been reported in multiple individuals with mild PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 27121329, 26322415, 16527067, 30050108, 28982351). This variant is absent in population databases (PM2). This variant was detected in trans with known pathogenic variants p.R261Ter (PMID: 27121329); c.611A>G (PMID: 30050108); p.S70del (PMID: 28982351) (PM3_strong). Computational evidence supports a deleterious effect (PP3). 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

Detected in trans with p.R261Ter (P, 5 submitters) PMID: 27121329; c.611A>G (P/LP, 4 submitters) PMID: 30050108; p.S70del (P, 3 submitters) PMID: 28982351

3 patients with p.Pro147Leu in trans with: S70del; p.His170Arg; p.Arg53His. Peripheral blood samples were collected from the patients and parents. Variable sites in patient genes were aligned with the corresponding sites from the respective parents. PubMed:28982351

Patient genotype: p.[Arg261*];[Pro147Leu]. Segregation analysis was done to rule out the presence of large genomic rearrangements. PubMed:27121329

Patient genotype: c.[440C>T ];[1215_1219delAATAC], p.[P147L];[I406Sfs*17]. 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. PubMed:26322415

From supplemental table: patient genotype p.P147L/c.611A>G (p.EX6-96A>G). The validation tests on parents were performed using Sanger sequencing. PubMed:30050108

PP3

Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen2, MutationTaster, REVEL=0.94)

PP4_Moderate

c.440C>T (p.P147L) identified in 1 patient with mild PKU. BH4 deficiency was excluded. PMID: 26322415

PubMed:26503515

c.440C>T (p.P147L) identified in 1 patient with mild PKU. All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. PubMed:26322415

PM2

Absent from controls in ExAC/gnomAD, 1000 Genomes, or ESP

Approved on: 2019-04-09

Published on: 2019-04-09

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