Submissions for variant NM_000277.3(PAH):c.682G>A (p.Glu228Lys)

dbSNP: rs281865444

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000106365	SCV001370841	uncertain significance	Phenylketonuria	2020-06-26	reviewed by expert panel	curation	The c.682G>A (p.Glu228Lys) variant in PAH has been reported in 1 individual with classic PKU detected with c.1066-11G>A. (PMID: 26666653). This variant has extremely low frequency in gnomAD. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3-supporting, PP3.
PreventionGenetics, part of Exact Sciences	RCV003398707	SCV004110976	uncertain significance	PAH-related disorder	2023-03-20	criteria provided, single submitter	clinical testing	The PAH c.682G>A variant is predicted to result in the amino acid substitution p.Glu228Lys. This variant, along with another variant in PAH, has been reported in an individual with phenylketonuria (Table 1, Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653) and was reported in a study of individuals with phenylketonuria, however no additional information was provided (Table S2, Hillert et al. 2020. PubMed ID: 32668217). Another variant impacting the same amino acid has been reported in a study of individuals with phenylketonuria [c.6847A>C (p.Glu228Asp), Additional File 2, Liu et al. 2017. PubMed ID: 28982351]. The c.682G>A (p.Glu228Lys) variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-103248938-C-T) and is interpreted as uncertain in ClinVar by a ClinGen expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/120284/). While this variant may be causative, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000106365	SCV004296168	pathogenic	Phenylketonuria	2023-08-23	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 120284). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu228 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 28982351), which suggests that this may be a clinically significant amino acid residue. 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 missense change has been observed in individual(s) with phenylketonuria (PMID: 26666653, 32668217; Invitae; BIOPKU http://www.biopku.org). This variant is present in population databases (rs281865444, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 228 of the PAH protein (p.Glu228Lys).
Inserm U 954, Faculté de Médecine de Nancy	RCV000106365	SCV000143865	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.