ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1243G>A (p.Asp415Asn) (rs62644499)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000401074 SCV000852091 pathogenic Phenylketonuria 2018-08-12 reviewed by expert panel curation The c.1243G>A (p.Asp415Asn) variant in PAH has been reported in 3 patients with Hyperphenylalaninemia (BH4 deficiency excluded). (PP4_Moderate; PMID: 1358789). This variant has an extremely low allele frequency (0.0001097 in gnomAD) (PM2; This variant was detected in trans with R408W, F39L, Y414C, IVS10-11G>A (Pathogenic in ClinVar) (PM3_Very-strong; PMID: 1358789; PMID: 12501224; PMID: 18299955). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong
GeneDx RCV000088815 SCV000239095 pathogenic not provided 2021-06-30 criteria provided, single submitter clinical testing Reported previously in association with mild hyperphenylalaninemia (Economou-Petersen et al., 1992; Guldberg et al., 1994; Trunzo et al., 2014); Functional studies found that this variant is associated with approximately 35% enzyme activity compared to wild-type (Himmelreich et al., 2018); Associated with BH4 responsiveness (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 30037505, 17935162, 31980526, 29499199, 29749107, 12501224, 27264808, 8088845, 24296287, 8929956, 11161839, 8406445, 9634518, 1358789, 22513348, 23500595)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000088815 SCV000331012 pathogenic not provided 2015-11-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000648 SCV000696434 pathogenic Hyperphenylalaninemia, non-pku 2016-08-04 criteria provided, single submitter clinical testing Variant summary: The PAH c.1243G>A (p.Asp415Asn) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 7/121346 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant has been reported in numerous individuals in the literature affected with mild-pku and mild-hyperphenylalaninemia, and has been associated with BH4 responsiveness. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000401074 SCV000834448 pathogenic Phenylketonuria 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 415 of the PAH protein (p.Asp415Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs62644499, ExAC 0.009%). This variant has been reported in combination with another heterozygous PAH variant in several individuals affected with mild phenylketonuria or mild hyperphenylalaninemia (PMID: 24296287, 18299955, 23932990, 1358789). ClinVar contains an entry for this variant (Variation ID: 617). Experimental studies have shown that this missense change mildly disrupts protein activity in vitro (PMID: 17935162). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000088815 SCV000888341 likely pathogenic not provided 2017-10-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000401074 SCV000893264 likely pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000401074 SCV000914552 pathogenic Phenylketonuria 2018-08-20 criteria provided, single submitter clinical testing Across a selection of available literature, the PAH c.1243G>A (p.Asp415Asn) missense variant has been identified in a compound heterozygous state in 19 patients (Economou-Petersen et al. 1992; Guldberg et al. 1994; Guldberg et al. 1995; Bercovich et al. 2008; Trunzo et al. 2014; Ho et al. 2014; Jeannesson-Thivisol et al. 2015). The p.Asp415Asn variant was absent from 220 controls and is reported at a frequency of 0.000358 in the Latino population of the Genome Aggregation Database. In vivo analysis of phenylalanine loading demonstrates that affected individuals with the p.Asp415Asn variant in a compound heterozygous state with a null PAH variant were able to clear the dose in 24 hours, which was consistent with the disease phenotype, and was established in several individuals affected by PAH deficiency (Economou-Petersen et al. 1992; Guldberg et al. 1995). Based on the evidence, the p.Asp415Asn 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.
Baylor Genetics RCV000401074 SCV001163709 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000401074 SCV001194126 pathogenic Phenylketonuria 2019-12-20 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.1243G>A(D415N) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and can be associated with variant or non-PKU hyperphenylalaninemia. Sources cited for classification include the following: PMID 1358789, 23500595, 24296287, 17935162, 12501224, 22513348, 9781015, 18299955, 18294361, 8088845 and 10234516. Classification of NM_000277.1(PAH):c.1243G>A(D415N) 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000088815 SCV001247318 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
OMIM RCV000000648 SCV000020798 pathogenic Hyperphenylalaninemia, non-pku 1992-09-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088815 SCV000119406 not provided not provided no assertion provided not provided
Natera, Inc. RCV000401074 SCV001458995 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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