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_000277.2(PAH):c.1200-1delG

CA229394

102564 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 835ba856-1559-4a87-b445-4fac9491c3f3

Approved on: 2022-12-09

Published on: 2022-12-09

HGVS expressions

NM_000277.2(PAH):c.1200-1delG

NC_000012.12:g.102840516del

CM000674.2:g.102840516del

NC_000012.11:g.103234294del

CM000674.1:g.103234294del

NC_000012.10:g.101758424del

NG_008690.1:g.82088del

NG_008690.2:g.122896del

ENST00000553106.6:c.1200del

ENST00000307000.7:c.1185del

ENST00000549247.6:n.959del

ENST00000551114.2:n.862del

ENST00000553106.5:c.1200del

ENST00000635477.1:n.304del

ENST00000635528.1:n.715del

NM_000277.1:c.1200del

NM_000277.2:c.1200del

NM_001354304.1:c.1200del

NM_000277.3:c.1200del

NM_001354304.2:c.1200del

Likely Pathogenic

PVS1_Strong PP4 PM2 PM3_Supporting

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.3(PAH):c.1200del variant (also reported as c.1200-1del) is a frameshift variant in exon 12 of 13 that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay, due to the resulting premature stop codon in exon 13, and therefore remove 0.4% of the protein. Exon 13 is considered a critical region because it (along with Exon 12) forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (PVS1_Strong). At least one patient (PMID: 8825461) with this variant had classic PKU with a serum phenylalanine level of 1468 umol/l (PP4). This patient is compound heterozygous for c.11200del and Arg408Trp (ClinVar 577, classified Pathogenic by the PAH VCEP) without confirmation of phase (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive phenylketonuria based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PP4, PM3_supporting, PM2. (PAH VCEP specifications version 1; date of approval xx/xx/xxxx).

PVS1_Strong

The c.1200del (p.Asn401Thrfs*51) variant in PAH is a frameshift variant in exon 12 of 13 that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay, due to the resulting premature stop codon in exon 13, and therefore remove 0.4% of the protein. Exon 13 is considered a critical region because it (along with Exon 12) forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (PVS1_Strong). This variant is also adjacent to the intron 11 splice acceptor site and may impact splicing resulting in skipping of exon 12. Both consequences were observed in patient cDNA.

PP4

At least one patient (PMID: 8825461) with this variant had classic PKU with a serum phenylalanine level of 1468 umol/l (above the >120 μmol/L requirement). Exclusion of a defect of BH4 cofactor metabolism was not reported. (PP4)

PM2

This variant is absent from gnomAD v2.1.1 (PM2).

PM3_Supporting

One patient in PMID: 31623983 is compound heterozygous for c.1200del and Arg408Trp (ClinVar 577, classified Pathogenic by the PAH VCEP), however, investigation of trans phase was not reported (PM3_supporting).

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