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

gnomAD frequency: 0.00091  dbSNP: rs118092776

Total submissions: 14

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).
GeneDx	RCV000088842	SCV000239059	uncertain significance	not provided	2024-05-07	criteria provided, single submitter	clinical testing	Reported primarily in association with a mild hyperphenylalaninemia (HPA) phenotype (PMID: 27173423, 23764561, 26322415, 23932990); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30747360, 17924342, 25087612, 27264808, 26666653, 28676969, 34704413, 20981092, 24082139, 26521805, 23764561, 26322415, 9452061, 17935162, 23932990, 29653233, 29499199, 29032371, 30512147, 30459323, 28982351, 29454221, 30050108, 29390883, 29353259, 24401910, 30945278, 31355225, 30275481, 34426522, 33465300, 35193651, 35095998, 35405047, 33161754, 36537053, 16253218, 34405919, 34662886, 36646061, 36845377, 36577126, 32668217, 32778825, 36246604, 27173423)
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490373	SCV000267433	uncertain significance	Phenylketonuria	2016-03-18	criteria provided, single submitter	reference population
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175359	SCV000696438	benign	not specified	2022-02-24	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 (gnomAD), predominantly at a frequency of 0.014 within the East Asian subpopulation in the gnomAD database, including 3 homozygotes. Ten homozygotes for c.158G>A have also been reported in individuals from the general Japanese population (Yamaguchi-Kabata_2019). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.158G>A has been reported in the literature in (mostly East Asian) individuals 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), with one report showing no clinical symptoms or signs of disease in 6 compound heterozygous patients identified during newborn screening and 1 homozygous parent, all of whom had blood Phe within the normal range while on a normal diet (e.g. Choi_2017). In multiple patients, the variant was reported in cis with another variant cited as pathogenic in ClinVar (e.g. Tao_2015, Odagiri_2021). 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. Su_2019, Odagiri_2021). At least one publication reports experimental evidence evaluating an impact on protein function, where the variant protein had 79% enzymatic activity relative to the wild type control (Liang_2014). Nine ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, two as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490373	SCV000754088	benign	Phenylketonuria	2024-01-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000490373	SCV001138806	uncertain significance	Phenylketonuria	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Genome-Nilou Lab	RCV000490373	SCV001716364	uncertain significance	Phenylketonuria	2021-05-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000490373	SCV003816612	uncertain significance	Phenylketonuria	2022-11-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398704	SCV004104616	uncertain significance	PAH-related disorder	2023-03-03	criteria provided, single submitter	clinical testing	The PAH c.158G>A variant is predicted to result in the amino acid substitution p.Arg53His. This variant has been documented as a common PAH variant in the Chinese population, and has been associated with mild hyperphenylalanemia (mHPA) (Park et al. 1998. PubMed ID: 9452061; Song et al. 2005. PubMed ID: 16256386; Liang et al. 2014 PubMed ID: 24401910; Lin et al. 2019. PubMed ID: 30904546). In a recent study of individuals identified by newborn genetic screening, 16 patients were identified with mildly elevated phenylalanine and the c.158G>A (p.Arg53His) variant on the opposite allele (in trans) from a pathogenic or likely pathogenic PAH variant (Huang et al. 2022. PubMed ID: 35193651). It should be noted that this particular variant has been reported to have an allele frequency of >1% in eastern Asian populations, including 3 homozygous individuals (http://gnomad.broadinstitute.org/variant/12-103306579-C-T) and has been suggested to be a likely benign variant based on higher allele frequencies in East Asian populations (Choi et al. 2017. PubMed ID: 29032371). While these higher allele frequencies would normally be considered too common for a recessive, pathogenic variant, the p.Arg53His amino acid change has been shown to only decrease the activity of the PAH protein to ~80% of wild-type (Liang et al. 2014. PubMed ID: 24401910). Such a modest effect on protein activity and the mild clinical phenotype associated with this variant may be consistent with this somewhat high allele frequency, and it is possible this variant may be causative for MHPA but is less likely to be causative for mild to classic phenylketonuria. This variant is currently interpreted as benign, likely benign, or uncertain in the ClinVar database, with the PAH Variant Curation Expert Panel interpreting it as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/102601/). Based on the collective evidence, we also interpret the clinical significance of this variant as uncertain.
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
Natera, Inc.	RCV000490373	SCV001455418	benign	Phenylketonuria	2020-01-06	no assertion criteria provided	clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000490373	SCV004800858	uncertain significance	Phenylketonuria		no assertion criteria provided	clinical testing	PM3_VS+PP3+PP4+BS1