Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

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
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Likely Pathogenic

Met criteria codes 3
PP4_Moderate PM2 PM3_Strong
Not Met criteria codes 2
PS3 PP3

Evidence Links 5

Expert Panel

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.
Met criteria codes
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
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
Not Met criteria codes
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
Curation History
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