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]

Variant: NM_000277.1(PAH):c.665A>T (p.Asp222Val)

Curation Version - 1.0
Curation History
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CA229681

102776 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2d746606-6991-490e-a6d3-9263659f37b8

Approved on: 2020-08-17

Published on: 2021-12-12

HGVS expressions

NM_000277.1:c.665A>T

NM_000277.1(PAH):c.665A>T (p.Asp222Val)

NC_000012.12:g.102855177T>A

CM000674.2:g.102855177T>A

NC_000012.11:g.103248955T>A

CM000674.1:g.103248955T>A

NC_000012.10:g.101773085T>A

NG_008690.1:g.67426A>T

NG_008690.2:g.108234A>T

ENST00000553106.6:c.665A>T

ENST00000307000.7:c.650A>T

ENST00000549111.5:n.761A>T

ENST00000553106.5:c.665A>T

NM_000277.2:c.665A>T

NM_001354304.1:c.665A>T

NM_000277.3:c.665A>T

NM_001354304.2:c.665A>T

NM_000277.3(PAH):c.665A>T (p.Asp222Val)

Likely Pathogenic

PP4_Moderate PP3 PM3 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.665A>T (p.Asp222Val) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21147011, 9012412). This variant is absent in population databases. This variant was detected with pathogenic variants p.R243X and p.R241H (PMID: 21147011). 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.

PP4_Moderate

D222V was found in 3 PKU patients. BH4 cofactor deficiency assessed in 2 patients by analysis of PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 21147011, PMID: 9012412

PKU patients from four centers in three countries of Great Britain were studied. D222V was seen in 1 patient from Southwestern England. PubMed:9012412

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). p.D222V found on 2 alleles in 2 patients. PubMed:21147011

PP3

Predicted deleterious in SIFT, Polyphen2, and MutationTaster, REVEL=0.938

PM3

D222V found with p.R243X and p.R241H, both Pathogenic in ClinVar. parental analysis not reported PMID: 21147011

D222V found in trans with p.R243X (VarID R243X, Pathogenic) in patient with classic PKU, and p.R241H (VarID 102804, Pathogenic) in another patient with mHPA. PubMed:21147011

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM5

p.Asp222Gly (VarID 102775) clinical significance not provided

Curation History

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