Submissions for variant NM_000277.3(PAH):c.232G>A (p.Glu78Lys)

dbSNP: rs62507326

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001857429	SCV005442781	likely pathogenic	Phenylketonuria	2024-11-17	reviewed by expert panel	curation	The c.232G>A (p.Glu78Lys) variant in PAH has been reported in at least two individuals with plasma Phe levels > 120 umol/L; in one patient, it was observed with c.194T>C (p.Ile65Thr) (classified as pathogenic by PAH VCEP Variation ID: 636) and in the other it was observed with c.1222C>T (p.Arg408Trp) (classified as pathogenic by PAH VCEP Variation ID: 577). Confirmation of phase and exclusion of BH4 deficiency were not specified (PMID: 23430918). c.232G>A has also been described without further information in two additional publications (PMID: 32668217, 32305867). Finally, c.232G>A has been observed in a patient with moderate PKU who also had c.1045T>C (p.Ser349Pro), which is not classified by the PAH VCEP (PMID: 31623983). In-vitro functional studies are unavailable. The Pop Max allele frequency is [8.476e-7] for [ENF] chromosomes by gnomAD v4.1.0, which is lower than the ClinGen PAH threshold (≤ 0.0002) for PM2_Supporting. In-silico predictions suggest this variant is pathogenic (REVEL=0.831). In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PP4, PM2-supporting, PP3-moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857429	SCV002301895	likely pathogenic	Phenylketonuria	2021-07-28	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102636). This missense change has been observed in individual(s) with PAH-related conditions and/or hyperphenylalaninemia (PMID: 32668217; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 78 of the PAH protein (p.Glu78Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088880	SCV000119477	not provided	not provided		no assertion provided	not provided