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.724C>T (p.Leu242Phe)

CA229718

102807 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 876bf9bc-abc3-4724-8777-4f61e10a4f76

HGVS expressions

NM_000277.1:c.724C>T

NM_000277.1(PAH):c.724C>T (p.Leu242Phe)

NC_000012.12:g.102852933G>A

CM000674.2:g.102852933G>A

NC_000012.11:g.103246711G>A

CM000674.1:g.103246711G>A

NC_000012.10:g.101770841G>A

NG_008690.1:g.69670C>T

NG_008690.2:g.110478C>T

ENST00000553106.6:c.724C>T

ENST00000307000.7:c.709C>T

ENST00000549247.6:n.483C>T

ENST00000553106.5:c.724C>T

NM_000277.2:c.724C>T

NM_001354304.1:c.724C>T

NM_000277.3:c.724C>T

NM_001354304.2:c.724C>T

NM_000277.3(PAH):c.724C>T (p.Leu242Phe)

Pathogenic

PP3 PM2 PM3_Very Strong PP4_Moderate

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.724C>T (p.Leu242Phe) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 1363786, 21147011). This variant is absent in population databases. It was detected with multiple pathogenic/likely pathogenic variants: p.R158Q (PMID: 24190797); IVS10-11G>A (PMID: 21147011); p.R252W (PMID: 1363786); p.V399V (PMID: 26600521); c.1315+4A>G (PMID: 25456745); p.R408W (PMID: 19244369); p.R241C (PMID: 30050108); c.1068C>A p.Tyr356* (2 patients), p.Arg243Gln (PMID: 28982351) 7.75 pts. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3.

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM3_Very Strong

L242F reported with 3 different variants. 2 are pathogenic (R158Q; IVS10-11G>A parental testing not reported PMID: 24190797,PMID: 21147011); 1 is P/LP (R252W) Restriction analysis of the PCR products demonstrated that the patient had inherited the mutation from his mother. PMID: 1363786; V399V (P 5 submitters). The variation sites of all patients’ sequences were compared to those of the parents, to determine the origin of sequence variability. PMID: 26600521; c.1315+4A>G (LP/P) parental analysis not reported PMID: 25456745; R408W parental analysis not reported PMID: 19244369; p.R241C (P 9 submitters)/p.L242F, validation tests on parents were performed using Sanger sequencing. PMID: 30050108; c.1068C>A p.Tyr356* (2 patients, P 7 submitters); p.Arg243Gln (P 11 submitters). variant sites in patient genes were aligned with the corresponding sites from the respective parents. PMID: 28982351 7.75 pts

Reported in 1 patient with IVS10-11G>A (VarID 607, Pathogenic) PubMed:21147011

L242F seen in 1 patient with R158Q (VarID 587, Pathogenic) PubMed:24190797

Patient B21-3 genotype L242F/R252W (VarID 584, Pathogenic/LP) PubMed:1363786

PP4_Moderate

Reported in multiple PKU patients. 1 report had ruled out BH4 deficiency with assessment of genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 1363786, PMID: 21147011

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). L242F seen on 1 allele. PubMed:21147011

Complete sequence analysis of 194 human PAH genes from classical PKU patients originating from West Germany and Bulgaria revealed 13 different mutations within exon 7 of the gene. L242F:CTC-->TTC seen on 1 allele in patient B21-3; Phe at detection 32.3 mg/dl. PubMed:1363786

PM5

No other variant in this codon in ClinVar

Approved on: 2020-09-14

Published on: 2021-12-12

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