rs5030856
Variant summary
Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PP4_ModeratePM2PM3
This summary comes from the ClinGen Evidence Repository: The c.1169A>G (p.Glu390Gly) variant in PAH has been reported on at least 47 alleles, most often with Mild Hyperphenylalaninemia. (BH4 deficiency excluded). (PP4_Moderate; PMID:8088845; PMID:21147011). This variant has an extremely low allele frequency (MAF=0.00018 in gnomAD) (PM2; http://gnomAD.broadinstitute.org). This variant was detected in trans with IVS-12nt1, L333F (Pathogenic in ClinVar) + 8 homozygotes (PM3_Very-strong; PMID:10479481; PMID:21147011; PMID:8088845). Computational prediction tools and conservation analysis suggest that the c.1169A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong LINK:https://erepo.genome.network/evrepo/ui/classification/CA114367/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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PAH | NM_000277.3 | c.1169A>G | p.Glu390Gly | missense_variant | Exon 11 of 13 | ENST00000553106.6 | NP_000268.1 | |
PAH | NM_001354304.2 | c.1169A>G | p.Glu390Gly | missense_variant | Exon 12 of 14 | NP_001341233.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000790 AC: 12AN: 151974Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000995 AC: 25AN: 251312Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135804
GnomAD4 exome AF: 0.000101 AC: 147AN: 1461624Hom.: 0 Cov.: 31 AF XY: 0.000118 AC XY: 86AN XY: 727116
GnomAD4 genome AF: 0.0000790 AC: 12AN: 151974Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6AN XY: 74236
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:12
Criteria applied: PM3_VSTR,PP4_MOD,PM2_SUP,PP3 -
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3_VS,PP3,PP4_M. -
This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 390 of the PAH protein (p.Glu390Gly). This variant is present in population databases (rs5030856, gnomAD 0.02%). This missense change has been observed in individual(s) with mild hyperphenylalaninemia and mild phenylketonuria (PMID: 8088845, 10472529, 10479481, 12655552, 17935162, 21147011, 21871829, 25596310, 26803807). 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: 625). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 17935162, 22300847, 26803807). For these reasons, this variant has been classified as Pathogenic. -
Across a selection of the available literature, the PAH c.1169A>G (p.Glu390Gly) missense variant has been identified in a compound heterozygous state in three individuals with phenylalanine hydroxylase deficiency and in one child with non-PKU hyperphenylalaninemia identified by newborn screening and in three individuals with mild hyperhpenylalaninemila. The variant was also identified in 23/630 alleles of individuals with BH4-responsive mild hyperhpenylalaninemila (Guldberg et al. 1994; Zurflüh et al. 2008; Couce et al. 2013; Trunzo et al. 2013). The p.Glu390Gly variant was absent from 110 controls and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Genome Aggregation Database. Averaged across different cell systems, the p.Glu390Gly variant showed 72.7% residual enzyme activity (Zurflüh et al. 2008), while expression in COS-7 cells revealed that the p.[Glu390Gly];[Arg408Trp] genotype, a recurrent genotype in European and Middle Eastern populations, showed 8.3% residual activity compared to wild type (Danecka et al. 2015). Based on the collective evidence, the p.Glu390Gly variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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The c.1169A>G (p.Glu390Gly) variant in PAH has been reported on at least 47 alleles, most often with Mild Hyperphenylalaninemia. (BH4 deficiency excluded). (PP4_Moderate; PMID: 8088845; PMID: 21147011). This variant has an extremely low allele frequency (MAF=0.00018 in gnomAD) (PM2; http://gnomAD.broadinstitute.org). This variant was detected in trans with IVS-12nt1, L333F (Pathogenic in ClinVar) + 8 homozygotes (PM3_Very-strong; PMID: 10479481; PMID: 21147011; PMID: 8088845). Computational prediction tools and conservation analysis suggest that the c.1169A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong -
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ACMG Criteria: PM2, PP3, PS3, PM3, PP5; Variant was found in heterozygous state -
not provided Pathogenic:5Other:1
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PP3, PM2, PM3_very_strong -
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as being a tetrahydrobiopterin (BH4) responsive variant (PMID: 17935162, 23559577); This variant is associated with the following publications: (PMID: 10472529, 25750018, 23500595, 34828281, 31355225, 26666653, 30963030, 21147011, 22763404, 25087612, 8088845, 11914042, 25596310, 8098245, 28676969, 24048906, 22300847, 15557004, 26803807, 10479481, 31589614, 34426522, 33375644, 32778825, 33465300, 29288420, 23792259, 23559577, 35355500, 36537053, 35328070, 35339094, 35405047, 17935162) -
The variant has been reported in multiple homozygous and compound heterozygous individuals affected with mild hyperphenylalaninemia or mild PKU and has been characterized as BH4-responsive in the published literature (PMID: 10472529 (1999), 19394257 (2009), 21147011 (2011), 22300847 (2012), 26803807 (2016), 31623983 (2019)). Functional studies have shown this variant reduces PAH activity to 42-62% (PMID: 21147011 (2011), 22300847 (2012), 26803807 (2016)). -
PAH: PM3:Very Strong, PM2, PS3:Moderate, PP4 -
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Hyperphenylalaninemia Pathogenic:2
Variant summary: The PAH c.1169A>G (p.Glu390Gly) variant involves the alteration of a conserved nucleotide, present in catalytic domain of the protein (Couce_2013) and is predicted to be damaging by 5/5 in silico tools. This variant was found in 12/121202 control chromosomes at a frequency of 0.000099, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant is widely described as one of the frequent pathogenic variants that causes hyperphenylalaninemia with consistent genotype-phenotype data and functional studies. Eight homozygotes with this variant were responsive to BH4 (Dobrowolski_2011) which can be attributed to mild functional effect of this variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
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PAH-related disorder Pathogenic:1
The PAH c.1169A>G variant is predicted to result in the amino acid substitution p.Glu390Gly. This variant has been mainly reported to be causative for mild hyperphenylalaninemia (HPA; Guldberg et al. 1994. PubMed ID: 8088845; Bénit et al. 1999. PubMed ID: 10479481; Dobrowolski et al. 2011. PubMed ID: 21147011; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). The p.Glu390Gly substitution has been reported to result in a PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). This variant has been classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel, as well as multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/625/). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Mild hyperphenylalaninemia Pathogenic:1
This sequence change in PAH is predicted to replace glutamic acid with glycine at codon 390, p.(Glu390Gly). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in BH4 AAA hydroxyl domain. There is a moderate physicochemical difference between glutamic acid and glycine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.016% (21/129,082 alleles) in the European (non-Finnish) population, which is consistent with phenylalanine hydroxylase deficiency. This variant has been detected in multiple individuals with mild hyperphenylalaninaemia (MHP) in the homozygous state and compound heterozygous with a second pathogenic allele. It is one of the most common variants associated with the MHP phenotype (PMID: 31623983, 32668217). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.973). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP3_Moderate, PM2_Supporting. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at