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_000277.3(PAH):c.514C>T (p.Gln172Ter)

CA229600

102718 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fdadac55-dae5-4d40-91a8-a88ff791c4f1

HGVS expressions

NM_000277.3:c.514C>T

NM_000277.3(PAH):c.514C>T (p.Gln172Ter)

NC_000012.12:g.102855328G>A

CM000674.2:g.102855328G>A

NC_000012.11:g.103249106G>A

CM000674.1:g.103249106G>A

NC_000012.10:g.101773236G>A

NG_008690.1:g.67275C>T

NG_008690.2:g.108083C>T

ENST00000553106.6:c.514C>T

ENST00000307000.7:c.499C>T

ENST00000549111.5:n.610C>T

ENST00000551988.5:n.535C>T

ENST00000553106.5:c.514C>T

NM_000277.1:c.514C>T

NM_000277.2:c.514C>T

NM_001354304.1:c.514C>T

NM_001354304.2:c.514C>T

Pathogenic

PP4_Moderate PVS1 PM3 PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.514C>T (p.Gln172Ter) variant in PAH was detected in multiple patients with PKU with pathogenic variants c.1315+1G>A (PMID:8889590) and p.Ala345Thr (PMID:28754886). This variant was absent in population databases. This was predicted as a null variant in PAH where LOF is a known mechanism of disease. This is a nonsense variant in exon 6 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, PM2, PP4_moderate.

PP4_Moderate

Variant was detected in multiple patients. One was affected with cPKU and the other was affected with mPKU. Those with BH4 cofactor deficiency were excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. PMID:8889590, 28754886

PVS1

Nonsense variant predicted to undergo NMD. Located in exon 6 out of 13 coding exons, not in the last 50bp of exon 12.

PM3

This variant was detected with the c.1315+1G>A pathogenic variant and the pathogenic variant p.Ala345Thr (PMID: 8889590, 28754886). points=1

PM2

This variant is absent from population databases gnomAD and ExAC.

Approved on: 2022-10-14

Published on: 2022-10-14

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