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

CA229531

102663 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

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

Approved on: 2022-10-14

Published on: 2022-10-14

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

• Met criteria codes: PVS1 PP4_Moderate PM3_Strong PM2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

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.

Met criteria codes

• 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.
• 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.
• 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.
• PM2: This variant is absent from population databases gnomAD and ExAC