Submissions for variant NM_000277.3(PAH):c.532G>A (p.Glu178Lys)

gnomAD frequency: 0.00001  dbSNP: rs1448720360

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001375893	SCV001572852	pathogenic	Phenylketonuria	2021-01-17	reviewed by expert panel	curation	The c.532G>A (p.Glu178Lys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 26503515; PMID: 26542770). This variant has an extremely low allele frequency (PopMax MAF=0.00006, ENF) in gnomAD (PM2). This variant was detected in trans with F39del (PMID: 26542770) (Pathogenic/Likely Pathogenic in ClinVar by 7 submitters, see ID 188933). It has also been observed with R408W (PMID: 28771436, parental testing not performed) (Pathogenic in ClinVar (ID 577) and by ClinGen PAH VCEP) and IVS4-1G>A (PMID: 29316886, parental testing unclear) (Pathogenic in ClinVar (ID 594) and by ClinGen PAH VCEP). Computational prediction tools and conservation analysis are conflicting. This is a novel missense change at an amino acid residue where a different pathogenic missense change has been seen before (c.533A>G (p.Glu178Gly). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong, PM2, PM5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193452	SCV001362286	uncertain significance	not specified	2019-06-11	criteria provided, single submitter	clinical testing	Variant summary: PAH c.532G>A (p.Glu178Lys) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 31380 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.532G>A, has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) or Hyperphenylalaninemia (Li_2015, Bayat_2016, Wang_2018, Razipour_2017). These reports do not provide unequivocal conclusions about association of the variant with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). One functional study showed that PAH protein with this variant had decreased expression in E.coli and cultured cells, however, the enzyme activity was not tested (Zong_2018). One study identified this variant in cis with p.Phe39del (pathogenic) in one patient (Rzaipour_2017). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. In addition, p.E178G, p.E178V have been reported to associate to disease in literatures, suggesting p.E178 is critical for PAH function. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until additional clinical and functional evidence become available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001375893	SCV002234026	pathogenic	Phenylketonuria	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 178 of the PAH protein (p.Glu178Lys). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of PAH-related conditions (PMID: 26542770, 28771436, 29653233). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 928885). 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 with a negative predictive value of 80%. Studies have shown that this missense change alters PAH gene expression (PMID: 29653233). This variant disrupts the p.Glu178 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7707686, 10479481, 26803807). 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.
Baylor Genetics	RCV001375893	SCV004201345	pathogenic	Phenylketonuria	2024-01-25	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001375893	SCV005416930	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_Strong+PP4_Moderate+PS3_Supporting+PM5
PreventionGenetics, part of Exact Sciences	RCV004740612	SCV005347678	pathogenic	PAH-related disorder	2024-05-29	no assertion criteria provided	clinical testing	The PAH c.532G>A variant is predicted to result in the amino acid substitution p.Glu178Lys. This variant has been reported in individuals with phenylketonuria, including at least one in whom it was detected in trans with a pathogenic variant (see, for example, Li et al. 2015. PubMed ID: 26503515; Bayat et al. 2016. PubMed ID: 26542770; Qian et al. 2017. PubMed ID: 28771436). This variant was identified on the same allele (in cis) with p.Phe39del in at least one individiual (Razipour et al. 2017. PubMed ID: 28676969). In vitro experimental studies indicated this variant decreased protein expression; however, enzyme activity was not measured (Zong et al. 2018. PubMed ID: 29653233). Another nucleotide change affecting the same amino acid (p.Glu178Gly) has also been reported in individuals with phenylketonuria (Goldberg et al. 1994. PubMed ID: 7707686). This variant is reported in 0.0065% of alleles in individuals of European (non-Finnish) descent in gnomAD. It is interpreted in ClinVar as uncertain by one submitter and pathogenic by three submitters, including the PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/928885/). This variant is interpreted as pathogenic.