rs62516152
Variant summary
Our verdict is Likely pathogenic. Variant got 4 ACMG points: 4P and 0B. PM3PP4_Moderate
This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PP4_Moderate: V2301 seen in 1 patient with PAH deficiency. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. (PMID:8268925); PM3_VeryStrong: Detected in trans with IVS 10-11G>A, L48S, R408W, E390G). Upgraded per ClinGen SVI Workgroup. (PMID:15943553; PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4_Moderate, PM3_VeryStrong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA286506/MONDO:0009861/006
Frequency
Consequence
ENST00000553106.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.688G>A | p.Val230Ile | missense_variant | 6/13 | ENST00000553106.6 | NP_000268.1 | |
PAH | NM_001354304.2 | c.688G>A | p.Val230Ile | missense_variant | 7/14 | NP_001341233.1 | ||
PAH | XM_017019370.2 | c.688G>A | p.Val230Ile | missense_variant | 6/7 | XP_016874859.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.688G>A | p.Val230Ile | missense_variant | 6/13 | 1 | NM_000277.3 | ENSP00000448059 | P1 | |
PAH | ENST00000549111.5 | n.784G>A | non_coding_transcript_exon_variant | 6/6 | 1 | |||||
PAH | ENST00000307000.7 | c.673G>A | p.Val225Ile | missense_variant | 7/14 | 5 | ENSP00000303500 |
Frequencies
GnomAD3 genomes AF: 0.000322 AC: 49AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000541 AC: 136AN: 251314Hom.: 0 AF XY: 0.000552 AC XY: 75AN XY: 135810
GnomAD4 exome AF: 0.000315 AC: 460AN: 1461696Hom.: 1 Cov.: 34 AF XY: 0.000366 AC XY: 266AN XY: 727174
GnomAD4 genome AF: 0.000322 AC: 49AN: 152290Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26AN XY: 74468
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:21
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 17, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 15, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Jul 26, 2022 | ACMG Criteria: PS3, PM3, PM5, PP2, PP5; Variant was found in compound heterozygous state with NM_000277.3:c.898G>T. - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 12, 2018 | PAH-specific ACMG/AMP criteria applied: PP4_Moderate: V2301 seen in 1 patient with PAH deficiency. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. (PMID:8268925); PM3_VeryStrong: Detected in trans with IVS 10-11G>A, L48S, R408W, E390G). Upgraded per ClinGen SVI Workgroup. (PMID:15943553; PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4_Moderate, PM3_VeryStrong). - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Nov 30, 2020 | This sequence change is predicted to replace valine with isoleucine at codon 230 of the PAH protein (p.Val230Ile). The valine residue is not conserved (100 vertebrates, UCSC), and is located in the catalytic Biopterin H domain. There is a small physicochemical difference between valine and isoleucine. The variant is present in a large population cohort at a frequency of 0.05% (rs62516152, 141/282,716 alleles, 0 homozygotes in gnomAD v2.1.1). It has consistently been identified in cases with mild hyperphenylalaninemia or mild phenylketonuria in the homozygous state or compound heterozygote with a second pathogenic allele (PMID: 18299955, 21871829, 23764561, 24048906 - PM3_VeryStrong). Cases have PAH deficiency with acquired hyperphenylalaninemia ruled out (PMID: 8268925 - PP4_Moderate). The average residual mutant enzyme activity is 63% (PMID: 11161839). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/7 algorithms). Additionally, a different missense change at the same residue (p.Val230Ala), determined to be likely pathogenic has been seen previously (PM5_Supporting). Based on the classification scheme RMH ACMG Guidelines v1.1.1 and disease-specific specifications from the PAH VCEP, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP4_Moderate, PM5_Supporting. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Mar 29, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 03, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 03, 2016 | Variant summary: The c.688G>A in PAH gene is a missense variant that involves a conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is present in the broad control population dataset of ExAC at a low frequency (0.042%), which does not exceed the maximum frequency for a pathogenic variant in PAH gene (0.79%). The variant has been reported in multiple pts presented with mild hyperphenylalaninemia or mild PKU with the remaining enzymatic activity being about 63% of normal. In general, patients with mild hyperphenylalaninemia do not require restrictive diet or supplementary treatment unless Phe concentrations reach the clinical threshold. Taken together, the variant was classified as Pathogenic for Mild Hyperphenylalaninemia. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 26, 2019 | NM_000277.1(PAH):c.688G>A(V230I) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency and can be associated with variant or non-PKU HPA. Sources cited for classification include the following: PMID 11161839, 21147011, 17924342, 23764561, 9012412, 17096675, 21871829, 11678552, 10679941, 16198137, 10598814, 10693064, 10234516, 12655553, 24048906, 18299955, 23500595, 23792259, 8088845, 8268925 and 10679941. Classification of NM_000277.1(PAH):c.688G>A(V230I) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Jan 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 08, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Feb 17, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM5_Supporting+PM3_VeryStrong+PP4_Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 230 of the PAH protein (p.Val230Ile). This variant is present in population databases (rs62516152, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hyperphenylalaninemia (HPA) or mild phenylketonuria (PKU) (PMID: 8268925, 10598814, 17096675, 17935162, 18299955, 23500595, 23792259, 24048906, 25087612; Invitae). 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: 102784). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2022 | The p.Val230Ile variant in PAH has been reported in at least 10 individuals with phenylalanine hydroxylase deficiency including several individuals who were compound heterozygotes with a pathogenic variant or were homozygous (Guldberg 1993 PMID: 8268925, Zaffanello 2005 PMID: 15943553, Zurflüh 2008 PMID: 17935162, Couce 2013 PMID: 23500595, Yan 2019 PMID: 30747360, Su 2019 PMID: 31355225). It has also been identified in 0.0866% (3/3472) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar as likely pathogenic by the ClinGen PAH Variant Curation Expert Panel using the . ACMG-AMP criteria specific for phenylalanine hydroxylase variants (Zastrow 2018 PMID: 30311390) and is curated in the FDA-recognized human genetic variant database (Variation ID 102784). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Another variant involving this codon (p.V230A) have been identified in individuals with phenylalanine hydroxylase deficiency and is classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylalanine hydroxylase deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PP4_Moderate, PM5_Supporting. - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Phenylketonuria (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 141 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated biopterin_H domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been classified as likely pathogenic by an expert panel in 2018 (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:4Uncertain:1Other:1
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | PAH: PM3:Very Strong, PP4:Moderate, PS3:Moderate, PM2:Supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 13, 2023 | PP4_moderate, PM3_very_strong - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2024 | Described as responsive to tetrahydrobiopterin (BH4) therapy (PMID: 17935162); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31998365, 23792259, 23500595, 32039316, 33101986, 32893076, 25087612, 21228398, 26990548, 11161839, 8088845, 8268925, 31355225, 30747360, 31980526, 30275481, 33465300, 31589614, 32668217, 32778825, z[case report], 34828281, 33564846, 31947737, 34405919, 18299955, 28182360, 35193651, 35405047, 34426522, 36537053, 17935162, 24048906, 23764561, 36646061, 36577126, 37257178, 38481932, 36787440, 39286960, 38731816, 38651393) - |
PAH-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 23, 2024 | The PAH c.688G>A variant is predicted to result in the amino acid substitution p.Val230Ile. This variant has been documented to be causative for hyperphenylalaninemia (for example, see Guldberg et al. 1993. PubMed ID: 8268925; Aulehla-Scholz et al. 2003. PubMed ID: 12655553; Bercovich et al. 2008. PubMed ID: 18299955; Supplemental Data for Hillert et al. 2020. PubMed ID: 32668217). Moreover, this variant has been reported to reduce the activity of the PAH protein to approximately 63% of wild-type (Bercovich et al. 2008. PubMed ID: 18299955; Couce et al. 2013. PubMed ID: 23500595) and the p.Val230Ile amino acid substitution has been reported to lead to a PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). The ClinGen PAH Variant Curation Expert Panel interprets this variant as likely pathogenic, and other laboratories have listed it in the ClinVar database as likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/102784/). Based on the available evidence, we classify the c.688G>A (p.Val230Ile) variant as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at