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.1030G>A (p.Gly344Ser)

CA229285

102479 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 38be7825-9c4d-48ac-9e48-ca5e8135e062

HGVS expressions

NM_000277.2:c.1030G>A

NM_000277.2(PAH):c.1030G>A (p.Gly344Ser)

ENST00000553106.6:c.1030G>A

ENST00000307000.7:c.1015G>A

ENST00000549247.6:n.789G>A

ENST00000551114.2:n.692G>A

ENST00000553106.5:c.1030G>A

ENST00000635477.1:n.134G>A

ENST00000635528.1:n.545G>A

NM_000277.1:c.1030G>A

NM_001354304.1:c.1030G>A

NM_000277.3:c.1030G>A

NM_001354304.2:c.1030G>A

NC_000012.12:g.102844371C>T

CM000674.2:g.102844371C>T

NC_000012.11:g.103238149C>T

CM000674.1:g.103238149C>T

NC_000012.10:g.101762279C>T

NG_008690.1:g.78232G>A

NG_008690.2:g.119040G>A

Likely Pathogenic

PP3 PP4_Moderate PM2 PM3

PM1 PM5

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1030G>A (p.Gly344Ser) variant in PAH has been reported in multiple individuals with PKU and mild PKU (BH4 deficiency excluded). (PMID: 26503515, 29390883, 9634518). This variant is absent in population databases. This variant was detected in trans with pathogenic variant p.Q419R (PMID: 26600521). Other missense changes at the same amino acid residue have been seen before (p.Gly344Asp, p.Gly344Arg, p.Gly344Val are Likely pathogenic by PAH VCEP). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.

PP3

Predicted deleterious by SIFT, Mutation Taster, Polyphen.

PP4_Moderate

found in multiple individuals with PKU and mild PKU in two studies. BH4 deficiency assesed with dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading. PMID: 26503515, 29390883, 9634518

Seen in a patient with PHE level of 2645.44, second mutation unknown. PubMed:29390883

found in an individual with mild PKU. PubMed:9634518

Found in one individual from China and one individual from Northern China. Both with PKU, identified using NGS. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PubMed:26503515

PM2

Absent in all population database.

PM3

Seen in trans with Q419R, P/LP in ClinVar. Parental analysis performed. PMID: 26600521

Seen in an individual and fetus in trans with Q419R. Not found in Clinvar. PubMed:26600521

PM1

Effects residue very close to active site.

Effects residue very close to active site. In vitro expression not available. PubMed:10980574

PM5

G344D/R found in Clinvar, but no classification provided. G344V curated as US in ClinVar, pathogenic by PAH VCEP.

Approved on: 2021-06-11

Published on: 2021-06-11

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