Submissions for variant NM_000277.3(PAH):c.169G>T (p.Glu57Ter)

dbSNP: rs140945592

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000106349	SCV001146717	pathogenic	Phenylketonuria	2019-09-29	reviewed by expert panel	curation	The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as 'literature only' and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The sequence change results in a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is present at extremely low frequencies in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP: the highest MAF reported is 0.00014 in Other subpopulation in gnomAD, below the 0.0002 allele frequency cutoff for PAH variants (PM2).
Inserm U 954, Faculté de Médecine de Nancy	RCV000106349	SCV000143848	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.