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]

Variant: NM_000277.3(PAH):c.587C>A (p.Ser196Tyr)

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Curation History
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CA16020823

556878 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9dc91cab-5019-4c50-8d99-ed271add7f91

Approved on: 2024-03-08

Published on: 2024-03-08

HGVS expressions

NM_000277.3:c.587C>A

NM_000277.3(PAH):c.587C>A (p.Ser196Tyr)

NC_000012.12:g.102855255G>T

CM000674.2:g.102855255G>T

NC_000012.11:g.103249033G>T

CM000674.1:g.103249033G>T

NC_000012.10:g.101773163G>T

NG_008690.1:g.67348C>A

NG_008690.2:g.108156C>A

ENST00000553106.6:c.587C>A

ENST00000307000.7:c.572C>A

ENST00000549111.5:n.683C>A

ENST00000553106.5:c.587C>A

NM_000277.1:c.587C>A

NM_000277.2:c.587C>A

NM_001354304.1:c.587C>A

NM_001354304.2:c.587C>A

Uncertain Significance

PP4 PM3 PM2_Supporting PS3_Supporting

PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.587C>A (p.Ser196Tyr) variant in PAH has been reported in one individual with mild hyperphenylalanemia, without exclusion of BH4 deficiency (PMID: 23792259). In this individual, c.587C>A occurred de novo on the paternal allele, with confirmation of paternity. c.842+3G>C was present on the maternal allele (classified as likely pathogenic by PAH VCEP, Variation ID: 102871). In-vitro studies show 21% enzyme activity (PMID: 27620137). This variant is present below the 0.0002 allele frequency threshold for PAH in population databases. Multiple lines of computational evidence yield conflicting predictions regarding the effect of this variant (REVEL=0.542). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PP4, PM2_supporting, PS3_supporting.

PP4

Mild HPA, plasma Phe 3 mg/dl at diagnosis. No documentation of exclusion of BH4 deficiency (PMID: 23792259).

PM3

Detected in trans with c.842+3G>C, classified as LP by PAH VCEP (Variation ID: 102871). PMID: 23792259

PM2_Supporting

Absent from controls in ExAC, 1000 Genomes, and ESP. Present in 1/113660 alleles in non-Finnish European population in gnomAD (allele frequency 0.00001, which is below the threshold of 0.0002).

PS3_Supporting

PAH enzyme activity 21% (PMID: 27620137). Method: "in vitro expression system in combination with liquid chromatography (LC) applied with electrospray ionization tandem mass spectrometry (ESI-MS-MS) for the quantification of tyrosine (Tyr) produced from phenylalanine (Phe) to assess the residual activities."

PP3

Conflicting predictions. Damaging in SIFT, benign in PolyPhen2, polymorphism in MutationTaster, REVEL=0.542.

Curation History

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