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_000277.2(PAH):c.833C>A (p.Thr278Asn)

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CA229802

102862 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: dd158492-c30e-4d9a-a0b3-eb26ae344b13

Approved on: 2020-10-29

Published on: 2022-02-20

HGVS expressions

NM_000277.2:c.833C>A

NM_000277.2(PAH):c.833C>A (p.Thr278Asn)

NC_000012.12:g.102852824G>T

CM000674.2:g.102852824G>T

NC_000012.11:g.103246602G>T

CM000674.1:g.103246602G>T

NC_000012.10:g.101770732G>T

NG_008690.1:g.69779C>A

NG_008690.2:g.110587C>A

ENST00000553106.6:c.833C>A

ENST00000307000.7:c.818C>A

ENST00000549247.6:n.592C>A

ENST00000553106.5:c.833C>A

NM_000277.1:c.833C>A

NM_001354304.1:c.833C>A

NM_000277.3:c.833C>A

NM_001354304.2:c.833C>A

NM_000277.3(PAH):c.833C>A (p.Thr278Asn)

Pathogenic

PM3_Strong PP4_Moderate PP3 PM5 PM2

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.833C>A (p.Thr278Asn) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded; PMID: 23764561, 16198137). This variant was detected with multiple pathogenic variants: p.R408W (PMID: 23764561); p.P281L (2 patients), and c.1315+1G>A (PMID: 23430918). This variant is absent in population databases Computational prediction tools and conservation analysis support a deleterious effect. Another missense change at the same amino acid (p.Thr278Ile) is pathogenic by 2 submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3.

PM3_Strong

Detected with R408W (VarID 577, Pathogenic in Clinvar) and P281L (VarID 589, Pathogenic in Clinvar), parental analysis not reported PMID: 23764561. 2 Italian patients with p.P281L, Canadian patient with c.1315+1G>A, paternal analysis not reported PMID: 23430918 2.0 pts

Found in trans with R408W (VarID 577, Pathogenic in Clinvar) and P281L (VarID 589, Pathogenic in Clinvar) PubMed:23764561

PP4_Moderate

Found in 2 Italian individuals with PKU, BH4 deficiency excluded (analysis of urinary pterins, and determination of DHPR activity in blood). PMID: 23764561, PMID: 16198137

Found in two individuals in trans with P281L and R408W. BH4 deficiency excluded. PubMed:23764561

Found in one individual with PKU, one exon 7, second mutation not reported. PubMed:8268925

PP3

Predicted deleterious by SIFT, PolyPhen2, and MutationTaster.

PM5

T278I predicted pathogenic by 2 submitters.

PM2

Absent in ExAC, 1000 genomes, ESP, and gnomAD.

Curation History

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