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_000277.1:c.1218A>G

CA6748708

552907 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 855d18fc-6dd6-4938-9924-d6694afb9079

Approved on: 2018-12-09

Published on: 2019-04-06

HGVS expressions

NM_000277.1:c.1218A>G

NC_000012.12:g.102840497T>C

CM000674.2:g.102840497T>C

NC_000012.11:g.103234275T>C

CM000674.1:g.103234275T>C

NC_000012.10:g.101758405T>C

NG_008690.1:g.82106A>G

NG_008690.2:g.122914A>G

NM_000277.2:c.1218A>G

NM_001354304.1:c.1218A>G

NM_000277.3:c.1218A>G

ENST00000307000.7:c.1203A>G

ENST00000551114.2:n.880A>G

ENST00000553106.5:c.1218A>G

ENST00000635477.1:n.322A>G

ENST00000635528.1:n.733A>G

Likely Pathogenic

PP4 PM5 PM3 PM2

PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1218A>G (p.Ile406Met) variant in PAH is reported in 2 individuals with non-PKU HPA. BH4 assessment was not stated. It was detected with a known pathogenic variant, p.Arg408Trp. (PMID: 23357515) This variant has a low allele frequency in gnomAD and ExAC (MAF=0.00003) and is absent in 1000G. Computational evidence is discordant. Another missense change at this amino acid is interpreted as likely pathogenic by the PAH VCEP (p.I406T). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PM5, PP4.

PP4

Seen in an individual with non HPA PKU or mild PKU. PMID: 23357515

Seen in an individual with non HPA PKU or mild PKU. Predicted to have a 'less deleterious' effect. PubMed:23357515

PM5

I406T curated as LP.

PM3

genotype p.[Ile406Met];[Arg408Trp] PMID: 23357515

2 patients with the genotype p.[Ile406Met];[Arg408Trp] (VarID 577, Pathogenic). PubMed:23357515

PM2

Low AF (gnomAD,ExAC MAF=0.00003) and absent in 1000G

PP3

Discordant results- tolerated by SIFT and damaging by PolyPhen and MutTaster

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