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_000277.1(PAH):c.635T>C (p.Leu212Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229668

102768 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2eaf4e3c-85c2-49cd-8343-42a8a9e94d1b

Approved on: 2021-07-17

Published on: 2021-09-06

HGVS expressions

NM_000277.1:c.635T>C

NM_000277.1(PAH):c.635T>C (p.Leu212Pro)

NC_000012.12:g.102855207A>G

CM000674.2:g.102855207A>G

NC_000012.11:g.103248985A>G

CM000674.1:g.103248985A>G

NC_000012.10:g.101773115A>G

NG_008690.1:g.67396T>C

NG_008690.2:g.108204T>C

ENST00000553106.6:c.635T>C

ENST00000307000.7:c.620T>C

ENST00000549111.5:n.731T>C

ENST00000553106.5:c.635T>C

NM_000277.2:c.635T>C

NM_001354304.1:c.635T>C

NM_000277.3:c.635T>C

NM_001354304.2:c.635T>C

Likely Pathogenic

PS3_Supporting PM3 PM2 PP4 PP3

PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.635T>C (p.Leu212Pro) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 9781015) detected with pathogenic variants: p.R408W (PMID: 17502162); p.R158Q (PMID: 23430918); c.1066-11G>A (PMID: 26666653). This variant is absent in population databases. In vitro residual activity of the p.L212P mutant enzyme is 17% of wild type, and it also showed reduced protein expression. Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PM2, PM3, PP3, PP4.

PS3_Supporting

In vitro residual activity of L212P is 17% of wild type. Also showed reduced protein expression. Investigated 8 variants.

Investigated 8 variants, including c.635T>C (p.L212P). We used an 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. The residual activity expressed as a percentage of the wild-type enzyme activity, was: 17.0 ± 7.0% (p.L212P). All of the PAH variant proteins with rather low activity (p.L212P, p.R270K and p.R261P) also exhibited reduced amounts of PAH protein, compared to wild-type. PubMed:27620137

PM3

detected with p.R408W(c.1222C>T) parental analysis not reported PMID: 17502162; p.R158Q parental analysis not reported PMID: 23430918; c.1066-11G>A] parental analysis not reported PMID: 26666653

PM2

Not found in ExAC, gnomAD, 1000G, or ESP

PP4

Found on 1 allele in PKU patient. No patient specific information reported (Phe level, 2nd mutation). BH4 deficiency not investigated. PMID: 9781015

We successfully analyzed 135 of 141 chromosomes from phenylketonuria (PKU) probands (95.7% of the sample), and eight additional chromosomes from a small number of probands with non-PKU hyperphenylalaninemia (HPA). L212P found on 0.7% of 135 alleles (1 allele). PubMed:9781015

PP3

Deleterious in SIFT, Polyphen2, MutationTaster

PM5

The current variant is the only variant found in this codon in ClinVar.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.