Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

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
Approved on: 2021-06-11
Published on: 2021-06-11

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
More

Likely Pathogenic

Met criteria codes 4
PP4_Moderate PP3 PM2 PM3
Not Met criteria codes 2
PM1 PM5

Evidence Links 5

Expert Panel

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.
Met criteria codes
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
PP3
Predicted deleterious by SIFT, Mutation Taster, Polyphen.
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
Not Met criteria codes
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.
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.