ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.158G>A (p.Arg53His) (rs118092776)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000490373 SCV000852170 uncertain significance Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01596 in ExAC (138/8648) and 0.0104 in gnomAD (265/18868 with 3 homozygotes); PP4: Detected in a patient with mild hyperphe (PMID:24401910); PM3: Detected with V388L (LP) (PMID:24401910). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, PP4, PM3).
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490373 SCV000267433 uncertain significance Phenylketonuria 2016-03-18 criteria provided, single submitter reference population
Integrated Genetics/Laboratory Corporation of America RCV001175359 SCV000696438 likely benign not specified 2019-12-26 criteria provided, single submitter clinical testing Variant summary: PAH c.158G>A (p.Arg53His) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251382 control chromosomes, predominantly at a frequency of 0.014 within the East Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.8- fold the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) phenotype (0.0079), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Ten homozygotes for c.158G>A have also been reported in individuals from the general Japanese population (Yamaguchi-Kabata_2019). c.158G>A has been reported in the literature in individuals (mostly East Asian ethnicity) affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and hyperphenylalaninemia(HPA) without strong evidence for causality (e.g. Park_1998, Liang_2014, Tao_2015, Zong_2018, Kuznetkova_2019, Lin_2019, Su_2019). These reports do not provide unequivocal conclusions about association of the variant with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). In multiple patients, the variant was reported in cis with another variant cited as pathogenic in ClinVar (c.842+2T>A, Tao_2015). One of these patients with classic PKU harbored a genotype of c.[331C>T];[158G>A;842 + 2T>A] (p.[R111*];[R53H;(?)]) that would support a diagnosis. In addition, the variant has been reported to co-occur with other pathogenic variants in PAH in individuals with PKU or HPA who were genotyped as either homozygotes or compound heterozygotes for other pathogenic variants that would be likely to explain the phenotype (e.g. p.R413P, p.A104D, p.V230I, c.842+2T>A, c.1066-11G>A; Su_2019) . At least one publication reports experimental evidence evaluating an impact on protein function. This study reported that the variant protein had 79% enzymatic activity relative to the wild type control (Liang_2014). Three clinical diagnostic laboratories and one expert panel (ClinGen PAH variant curation panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant as benign (n=1), likely benign (n=1) and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000490373 SCV000754088 benign Phenylketonuria 2019-12-31 criteria provided, single submitter clinical testing
Mendelics RCV000490373 SCV001138806 uncertain significance Phenylketonuria 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000490373 SCV001266460 likely benign Phenylketonuria 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088842 SCV000119435 not provided not provided no assertion provided not provided
SingHealth Duke-NUS Institute of Precision Medicine RCV000490373 SCV000853180 likely benign Phenylketonuria 2017-06-07 no assertion criteria provided curation

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