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.398_401del (p.Asn133fs)

CA229531

102663 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 026caaab-8228-4c63-a3ec-c32112612b17

HGVS expressions

NM_000277.3:c.398_401del

NM_000277.3(PAH):c.398_401del (p.Asn133fs)

NC_000012.12:g.102877504_102877507del

CM000674.2:g.102877504_102877507del

NC_000012.11:g.103271282_103271285del

CM000674.1:g.103271282_103271285del

NC_000012.10:g.101795412_101795415del

NG_008690.1:g.45098_45101del

NG_008690.2:g.85906_85909del

ENST00000553106.6:c.398_401del

ENST00000307000.7:c.383_386del

ENST00000549111.5:n.494_497del

ENST00000550978.6:n.382_385del

ENST00000551337.5:c.398_401del

ENST00000551988.5:n.487_490del

ENST00000553106.5:c.398_401del

NM_000277.1:c.398_401del

NM_000277.2:c.398_401del

NM_001354304.1:c.398_401del

NM_001354304.2:c.398_401del

Pathogenic

PP4_Moderate PM2 PM3_Strong PVS1

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.398_401del (p.Asn133fs) variant in PAH was detected with pathogenic and likely pathogenic variants in multiple patients with classic PKU and one with mild hyperphenylalaninemia (PMID: 22513348, 22526846, 8659548, 22917871, 26666653). This variant was absent in population databases. This is a frameshift variant in exon 4 of 13 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, PM2, PM3_Strong, PP4_moderate.

PP4_Moderate

Variant was detected in multiple patients with PKU. Those with BH4 cofactor deficiency were excluded by analysis of urinary pterins and dihydropterine reductase assays were performed. PMID: 22513348, 22526846,8659548, 22917871, 26666653.

PM2

This variant is absent from population databases gnomAD and ExAC

PM3_Strong

This variant was detected with p.R408W, p.R158Q, p.IVS10-3C>T, p.V245L, p.Arg68Ser, p.D415N pathogenic variants, and likely pathogenic variants p.P281L and IVS8-7A>G. PMID: 22513348, 22526846, 8659548, 22917871, 26666653. points=3.75.

PVS1

Frameshift variant predicted to undergo NMD. Termination occurs at position 194 (133+61). Located in exon 4 out of 13 coding exons, not in the last 50bp of exon 12.

Approved on: 2022-10-14

Published on: 2022-10-14

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