Submissions for variant NM_000277.3(PAH):c.688G>A (p.Val230Ile)

gnomAD frequency: 0.00029  dbSNP: rs62516152

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000411829	SCV000852131	likely pathogenic	Phenylketonuria	2018-08-12	reviewed by expert panel	curation	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).
GeneDx	RCV000089035	SCV000239065	likely pathogenic	not provided	2024-10-25	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411829	SCV000629205	pathogenic	Phenylketonuria	2025-01-12	criteria provided, single submitter	clinical testing	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; internal data). 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). 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: 11161839). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411829	SCV000696458	pathogenic	Phenylketonuria	2016-03-03	criteria provided, single submitter	clinical testing	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000411829	SCV000744097	pathogenic	Phenylketonuria	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000411829	SCV000745572	pathogenic	Phenylketonuria	2016-01-18	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000411829	SCV000746354	likely pathogenic	Phenylketonuria	2017-12-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000411829	SCV000893947	pathogenic	Phenylketonuria	2022-03-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411829	SCV001193891	likely pathogenic	Phenylketonuria	2019-12-26	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000089035	SCV001249183	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	PAH: PM3:Very Strong, PP4:Moderate, PS3:Moderate, PM2:Supporting
Genome-Nilou Lab	RCV000411829	SCV001737358	likely pathogenic	Phenylketonuria	2021-06-10	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000089035	SCV002009277	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000411829	SCV002016486	pathogenic	Phenylketonuria	2023-06-15	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000411829	SCV002028328	likely pathogenic	Phenylketonuria	2021-03-29	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000411829	SCV002503835	pathogenic	Phenylketonuria	2020-11-30	criteria provided, single submitter	clinical testing	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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000411829	SCV002570297	pathogenic	Phenylketonuria	2022-02-17	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000411829	SCV002581545	likely pathogenic	Phenylketonuria	2022-03-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000411829	SCV004201321	pathogenic	Phenylketonuria	2024-03-30	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000411829	SCV004804711	pathogenic	Phenylketonuria	2024-03-17	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000411829	SCV004848713	pathogenic	Phenylketonuria	2022-06-30	criteria provided, single submitter	clinical testing	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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000411829	SCV005051912	pathogenic	Phenylketonuria	2024-02-01	criteria provided, single submitter	curation
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000411829	SCV005086440	pathogenic	Phenylketonuria	2023-07-17	criteria provided, single submitter	clinical testing	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
Institute of Immunology and Genetics Kaiserslautern	RCV000411829	SCV005382220	pathogenic	Phenylketonuria	2022-07-26	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PM3, PM5, PP2, PP5; Variant was found in compound heterozygous state with NM_000277.3:c.898G>T.
Mayo Clinic Laboratories, Mayo Clinic	RCV000089035	SCV005414117	likely pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing	PP4_moderate, PM3_very_strong
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000411829	SCV005415810	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM5_Supporting+PM3_VeryStrong+PP4_Moderate
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000089035	SCV005624694	pathogenic	not provided	2024-07-09	criteria provided, single submitter	clinical testing	The PAH c.688G>A (p.Val230Ile) variant has been reported in the published literature in many individuals affected with mild hyperphenylalaninemia (MHP) as well as in those affected with moderate phenylketonuria (mPKU) (PMIDs: 16198137 (2005), 18299955 (2008), 21871829 (2011), 23764561 (2013), 24048906 (2014), 31355225 (2019), 31998365 (2019), 33101986 (2020)). This variant is associated with MHP, which is consistent with functional studies that have reported the variant to have reduced enzyme activity (63%) (PMID: 11161839 (2001), 38731816 (2024), and BIOPKU (http://www.biopku.org/)). The frequency of this variant in the general population, 0.0027 (28/10368 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089035	SCV000119640	not provided	not provided		no assertion provided	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000089035	SCV001740550	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398705	SCV004105907	likely pathogenic	PAH-related disorder	2024-08-23	no assertion criteria provided	clinical testing	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.