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_000277.3(PAH):c.1099dup (p.Leu367fs)

CA229342

102522 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e47a82f3-345d-4597-88be-ed161d371029

HGVS expressions

NM_000277.3:c.1099dup

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

NC_000012.12:g.102843750dup

CM000674.2:g.102843750dup

NC_000012.11:g.103237528dup

CM000674.1:g.103237528dup

NC_000012.10:g.101761658dup

NG_008690.1:g.78857dup

NG_008690.2:g.119665dup

ENST00000553106.6:c.1099dup

ENST00000307000.7:c.1084dup

ENST00000549247.6:n.858dup

ENST00000551114.2:n.761dup

ENST00000553106.5:c.1099dup

ENST00000635477.1:n.203dup

ENST00000635528.1:n.614dup

NM_000277.1:c.1099dup

NM_000277.2:c.1099dup

NM_001354304.1:c.1099dup

NM_001354304.2:c.1099dup

Pathogenic

PM2 PM3_Supporting PVS1 PP4

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.1099dup (p.Leu367Profs*27) 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: 16256386) with this variant in trans with Arg243Gln (ClinVar 591, Pathogenic by multiple submitters). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4.

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.

PM3_Supporting

The patient reported in PMID: 16256386 is reported compound heterozygous for c.1099dup and R243Q (ClinVar 591, Pathogenic by multiple submitters). Confirmation of trans phase was not reported. 0.5pt

PVS1

The c.1099dup (p.Leu367Profs*27) frameshift variant is in exon 11 where it creates a premature stop codon, which is predicted to result in NMD.

PP4

The patient reported in PMID: 16256386 has classic PKU with >1200 uM Phe.

Approved on: 2022-07-30

Published on: 2022-07-30

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