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.1099del (p.Leu367fs)

CA229343

102524 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c546e40c-fe7f-4472-bb60-9b71f887d4c2

HGVS expressions

NM_000277.3:c.1099del

NM_000277.3(PAH):c.1099del (p.Leu367fs)

NC_000012.12:g.102843750del

CM000674.2:g.102843750del

NC_000012.11:g.103237528del

CM000674.1:g.103237528del

NC_000012.10:g.101761658del

NG_008690.1:g.78857del

NG_008690.2:g.119665del

ENST00000553106.6:c.1099del

ENST00000307000.7:c.1084del

ENST00000549247.6:n.858del

ENST00000551114.2:n.761del

ENST00000553106.5:c.1099del

ENST00000635477.1:n.203del

ENST00000635528.1:n.614del

NM_000277.1:c.1099del

NM_000277.2:c.1099del

NM_001354304.1:c.1099del

NM_001354304.2:c.1099del

Pathogenic

PVS1 PM3_Supporting PP4_Moderate PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The frameshift variant c.1099del (HGVS nomenclature c.1095del) occurs in exon 11 of 13 and is predicted to result in NMD. The variant is found at an extremely low allele frequency of 0.000003980 overall in gnomAD with a MAF of 0.000008804 (1/113590) in the European population. One classical PKU patient has been reported (PMID: 29176022) with this variant in trans with Arg241Cys (ClinVar 102803, Pathogenic with expert panel review). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4_moderate.

PVS1

The c.1095del (p.Leu367Trpfs*33) frameshift variant (also known as c.1099del) is in exon 11 where it creates a premature stop codon, which is predicted to result in NMD.

PM3_Supporting

Patient 33 of PMID: 29176022 is compound heterozygous for the c.1099del variant and Arg241Cys (ClinVar 102803, Pathogenic with expert panel review). Confirmation of trans phase was not reported. 0.5pt

PP4_Moderate

Patient 33 of PMID: 29176022 has classic PKU with serum Phe levels >1200uM and exclusion of GH4 deficiency by urinary pterin analysis and a dihydropteridine reductase assay.

PM2

This variant is found at an extremely low allele frequency of 0.000003980 overall in gnomAD with a MAF of 0.000008804 (1/113590) in the European population.

Approved on: 2022-07-30

Published on: 2022-07-30

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