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.140C>T (p.Ala47Val)

CA114370

630 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b16a5fd2-c502-44ff-a982-59b607e2ca9b

Approved on: 2020-05-22

Published on: 2020-05-22

HGVS expressions

NM_000277.2:c.140C>T

NM_000277.2(PAH):c.140C>T (p.Ala47Val)

NC_000012.12:g.102912819G>A

CM000674.2:g.102912819G>A

NC_000012.11:g.103306597G>A

CM000674.1:g.103306597G>A

NC_000012.10:g.101830727G>A

NG_008690.1:g.9784C>T

NG_008690.2:g.50592C>T

NM_000277.1:c.140C>T

NM_001354304.1:c.140C>T

NM_000277.3:c.140C>T

NM_001354304.2:c.140C>T

ENST00000307000.7:c.125C>T

ENST00000546844.1:c.140C>T

ENST00000548677.2:n.227C>T

ENST00000548928.1:n.62C>T

ENST00000549111.5:n.236C>T

ENST00000550978.6:n.124C>T

ENST00000551337.5:c.140C>T

ENST00000551988.5:n.229C>T

ENST00000553106.5:c.140C>T

ENST00000635500.1:n.108C>T

Likely Pathogenic

PM2 PM3_Strong PP4_Moderate

PS3 PP3

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.140C>T (p.Ala47Val) variant in PAH has been reported in 3 individuals with MHP (BH4 deficiency excluded). (PMID: 24368688, 27121329). This variant has extremely low frequency in gnomAD MAF=0.00001. This variant was detected with pathogenic variants p.E280K (parental analysis not reported), p.Glu178Gly, c.1066-11G>A (segregation analysis done). Computational evidence is conflicting. 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.

PM2

extremely low frequency in GnomAD MAF=0.00001

PM3_Strong

p.E280K (P 9 submitters) parental analysis not reported PMID: 24368688 p.Glu178Gly (P 6 submitters) c.1066-11G>A (P 7 submitters) segregation analysis done PMID: 27121329

PubMed:24368688

PP4_Moderate

A47V in 2 patients with MHP phenylalanine levels <360 umol/liter. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and dihydropteridine reductase activity. PMID: 27121329

In Appdenxi, A47V classified as MHP variant PubMed:9634518

PubMed:23514811

PubMed:27121329

PS3

PMID 11326337: Binding studies showed that the wild-type form specifically binds phenylalanine, whereas A47V abolished or significantly reduced this phenylalanine-binding capacity.

To examine whether N-terminal PAH mutations affect the ability of PAH to bind phenylalanine at the regulatory domain, wild-type and five mutant (G46S, A47V, T63P/H64N, I65T, and R68S) forms of the N-terminal domain (residues 2-120) of human PAH were expressed as fusion proteins in Escherichia coli. Binding studies showed that the wild-type form of this domain specifically binds phenylalanine, whereas all mutations abolished or significantly reduced this phenylalanine-binding capacity. PubMed:11326337

PP3

Conflicting predictions of pathogenicity: SIFT-D Polyphen2-B MutationTaster-D REVEL=0.797

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.