ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.734T>C (p.Val245Ala) (rs76212747)

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Total submissions: 16
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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 2016-08-30 criteria provided, single submitter clinical testing The V245A variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. In vitro studies predict that V245A is associated with 50% residual phenylalanine hydroxylase activity and is classified as associated with a mild hyperphenylalaninemia (HPA) phenotype and BH4 responsiveness (Pey et al., 2007; Zurfluh et al., 2008).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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, non-pku 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
Invitae RCV000346938 SCV000833177 pathogenic Phenylketonuria 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 245 of the PAH protein (p.Val245Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs76212747, ExAC 0.1%). This variant has been reported in combination with a second variant in several individuals and families affected with hyperphenylalaninaemia (PMID: 8088845, 24296287, 25596310, 26803807). ClinVar contains an entry for this variant (Variation ID: 632). Experimental studies have shown that this missense change impairs PAH activity in vitro (PMID: 26803807). 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 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Women's Health, 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.
OMIM RCV000000664 SCV000020814 pathogenic Hyperphenylalaninemia, non-pku 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 RCV000148724 SCV000190456 uncertain significance Hyperphenylalaninaemia 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

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