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>A (p.Ala246Asp)

CA229726

102812 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 37207f14-d75f-4e73-af8d-9a2ac9d18ec6

Approved on: 2020-11-13

Published on: 2022-02-11

HGVS expressions

NM_000277.2:c.737C>A

NM_000277.2(PAH):c.737C>A (p.Ala246Asp)

NC_000012.12:g.102852920G>T

CM000674.2:g.102852920G>T

NC_000012.11:g.103246698G>T

CM000674.1:g.103246698G>T

NC_000012.10:g.101770828G>T

NG_008690.1:g.69683C>A

NG_008690.2:g.110491C>A

ENST00000553106.6:c.737C>A

ENST00000307000.7:c.722C>A

ENST00000549247.6:n.496C>A

ENST00000553106.5:c.737C>A

NM_000277.1:c.737C>A

NM_001354304.1:c.737C>A

NM_000277.3:c.737C>A

NM_001354304.2:c.737C>A

NM_000277.3(PAH):c.737C>A (p.Ala246Asp)

Uncertain Significance

PM3_Supporting PP4 PP3 PM2

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.737C>A (p.Ala246Asp) variant in PAH has been reported in 2 patients with PKU (PMID: 9012412,12173030), detected with pathogenic variant p.R408W in one patient (PMID: 31623983). This variant is absent in population databases. A deleterious effect is predicted by multiple lines of computational evidence. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3, PM3_supporting.

PM3_Supporting

p.R408W parental analysis not reported PMID: 31623983

PP4

Reported in 1 PKU patient from British Isles/Ireland. BH4 deficiency not excluded. PMID: 9012412, PMID: 12173030

Patients (n=386) were recruited to the study through the National Centre for Inherited Metabolic Disorders and the National Newborn Screening Programme at The Children’s Hospital. Initial diagnosis of hyperphenylalaninaemia was made on neonatal screening using the bacterial inhibition assay with confirmation by quantitative analysis of serum amino-acids. A246D seen on 1 allele. PubMed:12173030

PKU patients from four centers in three countries of Great Britain were studied. A246D was seen on 1 chromosome. PubMed:9012412

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.926

PM2

Absent from ExAC, 1000G, ESP, gnomAD

PM5

A246V is interpreted as uncertain significance by 1 submitter

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