ClinVar Miner

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

dbSNP: rs281865444
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Total submissions: 4
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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 ( and is interpreted as uncertain in ClinVar by a ClinGen expert panel ( 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.
Invitae RCV000106365 SCV004296168 pathogenic Phenylketonuria 2023-08-23 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 120284). This missense change has been observed in individual(s) with phenylketonuria (PMID: 26666653, 32668217; Invitae; BIOPKU 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.

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