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.1222C>T (p.Arg408Trp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA251523

577 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0dbc6b3d-662c-424c-bca8-7346f4312024

Approved on: 2018-08-06

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.1222C>T

NM_000277.1(PAH):c.1222C>T (p.Arg408Trp)

NC_000012.12:g.102840493G>A

CM000674.2:g.102840493G>A

NC_000012.11:g.103234271G>A

CM000674.1:g.103234271G>A

NC_000012.10:g.101758401G>A

NG_008690.1:g.82110C>T

NG_008690.2:g.122918C>T

NM_000277.2:c.1222C>T

NM_001354304.1:c.1222C>T

NM_000277.3:c.1222C>T

ENST00000307000.7:c.1207C>T

ENST00000551114.2:n.884C>T

ENST00000553106.5:c.1222C>T

ENST00000635477.1:n.326C>T

ENST00000635528.1:n.737C>T

Pathogenic

PP4_Moderate PS3 PP3 PM3_Strong

PM2

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PP3: ; PS3: PMID 17935162: Table 1: p.Arg408Trp 1.85% WT activity PMID 25596310: 1.3% activity of WT (Table S4) (PMID:25596310; PMID:17935162); PP4_Moderate: most common PAH mutation in cohort; exclude BH4 deficiency. (PMID:25596310; PMID:9634518); PM3_Strong: Detected with IVS12+1G>A, M1V (Pathogenic/LP) (PMID:9634518; PMID:1971147; PMID:1609797). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PS3, PP4_Moderate, PM3_Strong).

PP4_Moderate

most common PAH mutation in cohort; exclude BH4 deficiency.

PMID 9634518: exclude BH4 deficiency. Classified p.Arg408Trp as classic PKU variant. PubMed:9634518

PMID 25596310: most common PAH mutation in this cohort (Table 1). PubMed:25596310

PS3

PMID 17935162: Table 1: p.Arg408Trp 1.85% WT activity PMID 25596310: 1.3% activity of WT (Table S4)

PMID 25596310: 1.3% activity of WT (Table S4) PubMed:25596310

PMID 17935162: Table 1: p.Arg408Trp 1.85% WT activity PubMed:17935162

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3_Strong

Detected with IVS12+1G>A, M1V (Pathogenic/LP)

One French-Canadian proband of consanguineous parents (family 3; fig. 1) is homozygous for the R408W mutation on haplotype 1. PubMed:1971147

R408W/IVS12nt1g>a (VarID576, Pathogenic) PubMed:9634518

M1V mutation (VarID 586, P/LP) was found on four chromosomes, one of the compound heterozygotes also carried the R408W mutation (fig.1, patient P3). PubMed:1609797

PM2

ESP MAF=0.00174

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.