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

dbSNP: rs63186960

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV002509215	SCV002818525	likely pathogenic	Phenylketonuria	2022-12-09	reviewed by expert panel	curation	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).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088798	SCV000119386	not provided	not provided		no assertion provided	not provided