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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001354304.2:c.1242C>A

CA16020977

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b9b25ce7-98f8-4e3e-a418-20c6a270071c

HGVS expressions

NM_001354304.2:c.1242C>A

NC_000012.12:g.102840473G>T

CM000674.2:g.102840473G>T

NC_000012.11:g.103234251G>T

CM000674.1:g.103234251G>T

NC_000012.10:g.101758381G>T

NG_008690.1:g.82130C>A

NG_008690.2:g.122938C>A

ENST00000553106.6:c.1242C>A

ENST00000307000.7:c.1227C>A

ENST00000551114.2:n.904C>A

ENST00000553106.5:c.1242C>A

ENST00000635477.1:n.346C>A

ENST00000635528.1:n.757C>A

NM_000277.1:c.1242C>A

NM_000277.2:c.1242C>A

NM_001354304.1:c.1242C>A

NM_000277.3:c.1242C>A

Pathogenic

PVS1 PP4_Moderate PM2 PM3_Strong

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1242C>A (p.Tyr414Ter) variant in PAH was detected in multiple patients with PKU with the pathogenic variants p.Y204C (PMID: 24705691) and p.Arg241Cys (PMID: 28982351). This variant was absent in population databases. This is a nonsense variant in exon 12 of 13 coding exons predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3_Strong, PM2, PP4_Moderate.

PVS1

Nonsense variant predicted to undergo NMD. Located in exon 12 out of 13 coding exons, not in last 50bp of exon 12.

PP4_Moderate

Variant was detected in 2 patients affected with cPKU. BH4 deficiency was evaluated by the simultaneous measurement of amino acids (phenylalanine and tyrosine), pterins (neopterin and biopterin), loading test, and dihydropteridine reductase activity from a single specimen. PMID: 28982351, 24705691.

PM2

This variant is absent from population databases gnomAD and ExAC

PM3_Strong

This variant was detected p.Y204C in trans with the ClinVar reported pathogenic (reviewed by an expert panel) variant in a patient with cPKU and the ClinVar reported pathogenic (reviewed by an expert panel) variant p.Arg241Cys in a patient with PKU(PMID: 28982351, 24705691). points=2.

Approved on: 2022-10-14

Published on: 2022-10-14

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