Submissions for variant NM_000277.3(PAH):c.183C>G (p.Asn61Lys)

gnomAD frequency: 0.00001  dbSNP: rs199475634

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001199974	SCV001370796	likely pathogenic	Phenylketonuria	2020-04-10	reviewed by expert panel	curation	The c.183C>G (p.Asn61Lys) variant in PAH has been reported in 3 individuals with mild hyperphenylalaninaemia and mild PKU (BH4 deficiency excluded). (PMID: 10234516, 27121329). This variant is at extremely low frequency in ExAC: MAF=0.00017. This variant was detected with pathogenic variants p.R176L, IVS1nt5G>T (c.60+5G>T) and IVS10-11G>A (PMID: 10234516, 27121329). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001199974	SCV003441164	pathogenic	Phenylketonuria	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 61 of the PAH protein (p.Asn61Lys). This variant is present in population databases (rs199475634, gnomAD 0.01%). This missense change has been observed in individual(s) with mild hyperphenylalaninaemia (PMID: 10234516). ClinVar contains an entry for this variant (Variation ID: 102618). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function. This variant disrupts the p.Asn61 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12501224; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088860	SCV000119455	not provided	not provided		no assertion provided	not provided