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_000277.1(PAH):c.1222C>T (p.Arg408Trp)

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

PM3_Strong PP4_Moderate PP3 PS3

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).

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

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

PP3

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

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

PM2

ESP MAF=0.00174

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