Submissions for variant NM_000277.3(PAH):c.734T>C (p.Val245Ala)

gnomAD frequency: 0.00049  dbSNP: rs76212747

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000346938	SCV000852138	pathogenic	Phenylketonuria	2018-09-28	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM5: V245L Pathogenic; PP4_Moderate: Seen in at least 7 MHP patients. Exclusion of a defect in tetrahydrobiopterin metabolism. Upgraded per ClinGen Metabolic Workgroup. (PMID:7981714; PMID:9298832; PMID:9634518); PM3_VeryStrong: V245A detected with IVS-12nt1, R252W, L194P (both P/LP), R408W (Path). Upgraded per ClinGen SVI Workgroup (PMID:7981714; PMID:9298832; PMID:8088845). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM5, PP4_Moderate, PM3_VeryStrong).
GeneDx	RCV000089065	SCV000239069	pathogenic	not provided	2022-05-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate V245A is associated with residual phenylalanine hydroxylase enzyme activity (Zurfluh et al., 2008; Heintz et al., 2013; Danecka et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26666653, 24939588, 8739972, 10980574, 23559577, 25596310, 8088845, 17935162, 16601866, 25087612, 24055113, 24296287, 25637381, 12640344, 7981714, 9298832, 9781015, 8533759, 26803807, 26990548, 31980526, 33326653, 31589614, 32668217, 32778825)
Eurofins Ntd Llc (ga)	RCV000089065	SCV000331506	pathogenic	not provided	2015-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000664	SCV000696463	pathogenic	Hyperphenylalaninemia	2017-04-13	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.734T>C (p.Val245Ala) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 86/121256 control chromosomes at a frequency of 0.0007092, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in many HPA alleles worldwide and functional studies showed variant with ~ 50% residue activity, which explains the mild phenotype of patients with this variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000346938	SCV000744096	pathogenic	Phenylketonuria	2014-10-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000346938	SCV000833177	pathogenic	Phenylketonuria	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 245 of the PAH protein (p.Val245Ala). This variant is present in population databases (rs76212747, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hyperphenylalaninaemia (PMID: 8088845, 24296287, 25596310, 26803807). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 632). 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: 26803807). This variant disrupts the p.Val245 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11161839, 15159646). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000089065	SCV000888352	pathogenic	not provided	2018-07-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000346938	SCV000893945	pathogenic	Phenylketonuria	2022-03-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000346938	SCV000915571	pathogenic	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing	The PAHc.734T>C (p.Val245Ala) missense variant has been reported in four studies in which it is identified in a compound heterozygous state in a total of eight individuals with phenylalanine hydroxylase deficiency (Gulberg et al. 1994; Zekanowski et al 1997; Kasnauskiene et al. 2003; Trunzo et al. 2014). The p.Val245Ala variant was absent from 220 control chromosomes and is reported at a frequency of 0.00114 in the European (non-Finnish) population of the Exome Aggregation Consortium. Danecka et al. (2015) provided functional assessment of a variety of PAH variants co-expressed in COS-7 cells, and demonstrated reduced activity of the p.Val245Ala variant as compared to wild type. Based on the collective evidence, the p.Val245Ala 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.
Myriad Genetics, Inc.	RCV000346938	SCV001193787	pathogenic	Phenylketonuria	2019-12-17	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.734T>C(V245A) is classified as 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 10394930, 16198137, 24350308, 11161839, 16198137, 9781015, 12655553, 23764561, 8088845 and 12501224. Classification of NM_000277.1(PAH):c.734T>C(V245A) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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.
Revvity Omics, Revvity	RCV000346938	SCV002016476	pathogenic	Phenylketonuria	2021-04-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000346938	SCV002768552	pathogenic	Phenylketonuria	2024-09-21	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 alanine. (I) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (130 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (6 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated biopterin H domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternative changes p.(Val245Leu) and p.(Val245Glu) have been reported as pathogenic in patients with phenylketonuria (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in patients with mild phenylketonuria (ClinVar, PMID: 26666653). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002512615	SCV003712587	pathogenic	Inborn genetic diseases	2021-01-21	criteria provided, single submitter	clinical testing	The c.734T>C (p.V245A) alteration is located in exon 7 (coding exon 7) of the PAH gene. This alteration results from a T to C substitution at nucleotide position 734, causing the valine (V) at amino acid position 245 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD) database, the PAH c.734T>C alteration was observed in 0.05% (130/282610) of total alleles studied, with a frequency of 0.09% (112/128966) in the European (non-Finnish) subpopulation. This common mutation and has been detected in combination with a second variant in many individuals affected with nonphenylketonuria hyperphenylalaninemia and mild hyperphenylalaninemia (Guldberg, 1994; Ald&aacute;miz-Echevarr&iacute;a, 2016; Tolve, 2018). This amino acid position is completely conserved on sequence alignment. In vitro functional studies have shown that this alteration impairs PAH (phenylalanine hydroxylase) activity (Shen, 2016; Danecka, 2015). The p.V245A alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000346938	SCV004201340	pathogenic	Phenylketonuria	2024-03-27	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000089065	SCV005197066	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000000664	SCV000020814	pathogenic	Hyperphenylalaninemia	1994-05-15	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089065	SCV000119671	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000000664	SCV000190456	uncertain significance	Hyperphenylalaninemia	2014-06-01	no assertion criteria provided	research
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000346938	SCV000536874	likely pathogenic	Phenylketonuria	2016-03-16	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000346938	SCV000733124	likely pathogenic	Phenylketonuria		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000346938	SCV001453111	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000089065	SCV001964069	likely pathogenic	not provided		no assertion criteria provided	clinical testing