Submissions for variant NM_000277.3(PAH):c.1194A>G (p.Lys398=)

dbSNP: rs199475638

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001269042	SCV001448233	likely pathogenic	Phenylketonuria	2020-09-12	reviewed by expert panel	curation	The c.1194A>G (p.Lys398Lys) variant in PAH has been reported in 1in 2 Chinese patients with moderate/classic PKU and BH4 deficiency excluded. (PMIDs: 25894915, 28982351; PP4_Moderate). Both patients were compound heterozygotes with pathogenic variants R413P and R241C confirmed in trans (PM3_Strong). This variant is present at an extremely low frequency with a MAF of 0.00005438 in the gnomAD East Asian population. (PM2). There is consensus of computational predictors that there is potential alteration of splicing via activation of a cryptic splice site near the end of exon 11.In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Strong, PP3, PP4_Moderate.
Invitae	RCV001269042	SCV004294260	pathogenic	Phenylketonuria	2023-06-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 102550). This variant has been observed in individual(s) with phenylketonuria (PMID: 25894915, 32668217). This variant is present in population databases (rs199475638, gnomAD 0.006%). This sequence change affects codon 398 of the PAH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PAH protein.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088784	SCV000119371	not provided	not provided		no assertion provided	not provided