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]

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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

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

NM_000277.3(PAH):c.737C>T (p.Ala246Val)

Uncertain Significance

PP3 PM2 PP4_Moderate

PM5

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

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.

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.932

PM2

Absent from 1000G. Extremely low frequency in ExAC, gnomAD (MAF=0.00001), ESP

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

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

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

PM5

A246D is interpreted as VUS by PAH VCEP

Approved on: 2020-11-13

Published on: 2022-03-11

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