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_000277.3(PAH):c.1171A>G (p.Ser391Gly)

CA267630

120261 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5373f3dd-e147-4449-974f-e804720298ee

HGVS expressions

NM_000277.3:c.1171A>G

NM_000277.3(PAH):c.1171A>G (p.Ser391Gly)

NC_000012.12:g.102843674T>C

CM000674.2:g.102843674T>C

NC_000012.11:g.103237452T>C

CM000674.1:g.103237452T>C

NC_000012.10:g.101761582T>C

NG_008690.1:g.78929A>G

NG_008690.2:g.119737A>G

NM_000277.1:c.1171A>G

NM_000277.2:c.1171A>G

NM_001354304.1:c.1171A>G

NM_001354304.2:c.1171A>G

ENST00000307000.7:c.1156A>G

ENST00000549247.6:n.930A>G

ENST00000551114.2:n.833A>G

ENST00000553106.5:c.1171A>G

ENST00000635477.1:n.275A>G

ENST00000635528.1:n.686A>G

Uncertain Significance

PM2 PM5 PP3

PM3 PP4

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1171A>G (p.Ser391Gly) variant in PAH has been reported in at least 1 individual with classic PKU (PMID: 26666653). However, the patient genotype included pathogenic variants c.194 T >C; p.Ile65Thr (ClinVar: 636), c.1169A >G; p.Glu390Gly (ClinVar: 625), and this variant c.1171A >G (p.Ser391Gly) with phasing not confirmed. This variant was absent in population databases (PM2). Computational prediction tools suggest that the c.1171A>G variant may impact the protein (PP3). The alternate missense changes of Ser391Ile (interpreted as Pathogenic by the ClinGen PAH Expert Panel) and Ser391Thr (ClinVar 225136, Likely Pathogenic) have been reported at the same amino acid residue (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3.

PM2

This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

PM5

Ser391Ile (Pathogenic by the ClinGen PAH Expert Panel) and Ser391Thr (Likely Pathogenic) have been reported at the same amino acid residue.

PP3

Predicted damaging by SIFT, Polyphen2, Mutation Taster, and REVEL = 0.938

PM3

Detected with pathogenic variants c.194 T >C; p.Ile65Thr (P 9 submitters), and1169A >G; p.Glu390Gly (P 7 submitters) in the same patient. The phase of the variants was not confirmed.

PP4

At least one patient with classic PKU phenotype and PHE >1200 umol/L has been reported (PMID: 26666653). Defects in BH4 cofactor metabolism were not reported to have been excluded. However, patient genotype listed both E390G and I65T with pasing not confirmed.

Approved on: 2020-04-10

Published on: 2020-04-10

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