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.242C>A (p.Thr81Asn)

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Curation History
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CA275937

208180 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 50209afd-af57-49df-9248-edd2fd6d5cab

Approved on: 2018-12-10

Published on: 2019-04-06

HGVS expressions

NM_000277.2:c.242C>A

NM_000277.2(PAH):c.242C>A (p.Thr81Asn)

NC_000012.12:g.102894845G>T

CM000674.2:g.102894845G>T

NC_000012.11:g.103288623G>T

CM000674.1:g.103288623G>T

NC_000012.10:g.101812753G>T

NG_008690.1:g.27758C>A

NG_008690.2:g.68566C>A

NM_000277.1:c.242C>A

NM_001354304.1:c.242C>A

NM_000277.3:c.242C>A

ENST00000307000.7:c.227C>A

ENST00000546844.1:c.242C>A

ENST00000548677.2:n.329C>A

ENST00000548928.1:n.164C>A

ENST00000549111.5:n.338C>A

ENST00000550978.6:n.226C>A

ENST00000551337.5:c.242C>A

ENST00000551988.5:n.331C>A

ENST00000553106.5:c.242C>A

Likely Pathogenic

PP3 PP4_Moderate PM2 PM3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.242C>A (p.Thr81Asn) variant in PAH is reported in 1 PKU patient. PAH and BH4DH genes were sequenced. It was detected with p.V230I which is interpreted as Pathogenic/Likely Pathogenic in ClinVar. (PMID: 23942198) This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, MutationTaster, and Polyphen-2. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3, PP3.

PP3

Deleterious effect predicted in SIFT, MutationTaster, Polyphen-2 (P when manually queried)

PP4_Moderate

T81N detected in 1 PKU patient sample. PAH and BH4DH genes were sequenced. PMID: 23942198

High-quality genomic DNA from 107 unrelated samples (106 PKU and BH4DH patients and one control sample) was obtained. The validation cohort included 95 patients and one control sample that had previously undergone conventional biochemical and genetic diagnosis at the Centro de Diagnóstico de Enfermedades Moleculares (CEDEM) in Madrid, Spain, and all disease-causing mutations in PAH, GCH1, PTS, and QDPR were confirmed using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA), except in the case of patient H8, for whom the second PAH allele was unknown. Sample D10: p.T81N on allele1 and p.(V230I) on allele 2. PubMed:23942198

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM3

Detected with V230I (P/LP) PMID: 23942198

Sample D10: p.T81N on allele1 and p.(V230I) on allele 2. PubMed:23942198

Curation History

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