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.143T>C (p.Leu48Ser)

CA251539

608 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d9c8f867-8d78-48cd-8299-827206594d17

Approved on: 2019-04-08

Published on: 2019-04-08

HGVS expressions

NM_000277.2:c.143T>C

NM_000277.2(PAH):c.143T>C (p.Leu48Ser)

NC_000012.12:g.102912816A>G

CM000674.2:g.102912816A>G

NC_000012.11:g.103306594A>G

CM000674.1:g.103306594A>G

NC_000012.10:g.101830724A>G

NG_008690.1:g.9787T>C

NG_008690.2:g.50595T>C

NM_000277.1:c.143T>C

NM_001354304.1:c.143T>C

NM_000277.3:c.143T>C

ENST00000307000.7:c.128T>C

ENST00000546844.1:c.143T>C

ENST00000548677.2:n.230T>C

ENST00000548928.1:n.65T>C

ENST00000549111.5:n.239T>C

ENST00000550978.6:n.127T>C

ENST00000551337.5:c.143T>C

ENST00000551988.5:n.232T>C

ENST00000553106.5:c.143T>C

ENST00000635500.1:n.111T>C

Pathogenic

PP4_Moderate PS3 PP3 PP1 PM3

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.143T>C (p.Leu48Ser) variant in PAH has been reported multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 26322415, 16879198, 1679030). This variant has a frequency that is higher than the suggested cutoff for PM2 by the PAH VCEP (MAF=0.00026). This variant has 39% residual activity (PS3, PMID: 17935162). This variant was detected in trans with p.G247R (LP, 2 submitters) PM3, PMID: 26322415). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Cosegregation with PKU in 2 siblings for 2 unrelated families was reported ( PMID: 23430547). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3, PP1, PP3.

PP4_Moderate

Detected in multiple patients with PKU (mild and classic). Bh4 deficiency excluded. PMID: 26322415, PMID: 16879198, PMID: 1679030

L48S was detected on 1 allele. 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

Using both polymerase chain reaction-restriction fragment length polymorphism and 'broad-range' denaturing-gradient gel electrophoresis/DNA sequencing analysis, 19 disease-causing mutations were identified, corresponding to mutation detection rate of 97%. The most frequent ones were L48S (21%). We found that the most frequent mutation, L48S, was exclusively associated with the classical (severe) PKU phenotype. PubMed:16879198

Detected in a Turkish patient with classic PKU. PubMed:1679030

PS3

p.L48S, c.143T>C has 39% residual activity PMID: 17935162

Table 1: p.L48S, c.143T>C has 39% residual activity PubMed:17935162

PP3

Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen2, MutationTaster, REVEL=0.97)

PP1

Cosegregation with PKU in 2 siblings for 2 unrelated families PMID: 23430547

Siblings (Patient 17 and 18) with classic PKU and genotype p.[L48S];[S231F]. Siblings (Patient 13 and 14) with mild PKU and homozygous genotype. PubMed:23430547

PM3

detected in trans with p.G247R (LP, 2 submitters) PMID: 26322415

Patient genotype: c.[143T>C];[739G>C], p.[L48S];[G247R] (LP, 2 submitters). 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

PM2

MAF=0.00026 in gnomAD is higher than PAH VCEP threshold (<0.0002) for PM2

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