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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!
  • See Evidence submitted by expert panel for details.

Variant: NM_000277.2(PAH):c.737C>T (p.Ala246Val)

CA229727

102813 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 160d0bef-780b-4613-8966-ecf9eb1ffef0
Approved on: 2020-11-13
Published on: 2022-03-11

HGVS expressions

NM_000277.2:c.737C>T
NM_000277.2(PAH):c.737C>T (p.Ala246Val)
NC_000012.12:g.102852920G>A
CM000674.2:g.102852920G>A
NC_000012.11:g.103246698G>A
CM000674.1:g.103246698G>A
NC_000012.10:g.101770828G>A
NG_008690.1:g.69683C>T
NG_008690.2:g.110491C>T
ENST00000553106.6:c.737C>T
ENST00000307000.7:c.722C>T
ENST00000549247.6:n.496C>T
ENST00000553106.5:c.737C>T
NM_000277.1:c.737C>T
NM_001354304.1:c.737C>T
NM_000277.3:c.737C>T
NM_001354304.2:c.737C>T
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Uncertain Significance

Met criteria codes 3
PP4_Moderate PP3 PM2
Not Met criteria codes 1
PM5

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The c.737C>T (p.Ala246Val) variant in PAH has been reported in multiple patients with PAH deficiency (BH4 deficiency excluded in one patient) (PMID: 9634518, 10394930, 12655553, 30747360) This variant is absent from 1000G, and at extremely low frequency in gnomAD (MAF=0.00001) and ESP. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3.
Met criteria codes
PP4_Moderate
A246V seen in 1 patient with mild PKU from Germany. PMID: 9634518, PMID: 10394930, PMID: 12655553. Also reported in a patient from China with MHP (All patients were excluded from tetrahydrobiopterin deficiency through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay on DBS samples) PMID: 30747360
Seven centers in France, Italy, Belgium, Germany, and Denmark participated in this collaborative study. A246V was seen in 1 Mild PKU patient. Patients with mild PKU tolerate 25–50 mg/kg body wt/d (400–600 mg/d). PubMed:9634518
A total of 226 families with PAH deficiency (212 patients, 14 heterozygous relatives) and 170 individuals without family history of PKU (partners of PKU patients or of heterozygotes) of German descent were analysed. A246V was found on a single chromosome. PubMed:12655553
Patients with PAH-deficient hyperphenylalaninaemia in 272 independent families (248 PKU and 24 MHP) living in Germany were investigated, including most patients of the German Collaborative PKU Study (Lutz et al. 1990). A246V (c.737C→T) seen in 1 patient. PubMed:10394930
PP3
Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.932
PM2
Absent from 1000G. Extremely low frequency in ExAC, gnomAD (MAF=0.00001), ESP
Not Met criteria codes
PM5
A246D is interpreted as VUS by PAH VCEP
Curation History
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