Submissions for variant NM_000277.3(PAH):c.464G>A (p.Arg155His)

gnomAD frequency: 0.00003  dbSNP: rs199475663

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000632881	SCV001146729	pathogenic	Phenylketonuria	2019-04-07	reviewed by expert panel	curation	The c.464G>A (p.Arg155His) has been reported in multiple individuals with mild hyperphenylalaninaemia, with BH4 deficiency excluded including 3 siblings (PP4_moderate, PMID: 9634518; PP1, PMID:18937047). This variant has low frequency in ExAC/gnomad (MAF=0.00012) in EA population (PM2). Multiple lines of computational evidence support a deleterious effect (PP3). This variant has been detected with 3 pathogenic variants: R243Q (PMID: 23932990), R111X (PMID: 24401910), IVS4+5G>T c.441+5G>T (PMID: 26210745) (PM3-strong). Experimental study showed the R155H mutant retained 55% activity, but this is higher than the cutoff set by PAH VCEP for PS3. (PMID: 18937047). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong, PM2, PP3, PP1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632881	SCV000754082	pathogenic	Phenylketonuria	2025-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 155 of the PAH protein (p.Arg155His). This variant is present in population databases (rs199475663, gnomAD 0.01%). This missense change has been observed in individual(s) with hyperphenylalaninaemia and/or phenylketonuria (PMID: 18937047, 23932990, 24401910, 26210745, 28754886). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 102686). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 18937047). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000632881	SCV001361064	pathogenic	Phenylketonuria	2019-06-11	criteria provided, single submitter	clinical testing	Variant summary: PAH c.464G>A (p.Arg155His) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase domain (IPR019774) 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 2e-05 in 251348 control chromosomes. c.464G>A has been reported in the literature in multiple individuals affected with Hyperphenylalaninemia (Guldberg_1998, Dobrowolski_2009) and Phenylketonuria (Trunzo_2015, Baturina_2016). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (Dobrowolski_2009, Himmelreich_2018) . The most pronounced variant effect results in 10%-<30% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000088934	SCV001813037	pathogenic	not provided	2020-12-08	criteria provided, single submitter	clinical testing	R155H classified as variant associated with mild hyperphenylalaninemia (Guldberg et al., 1998), however it has been reported in patients with mild and classic PKU (Dobrowolski et al., 2011; Zhu et al., 2013); In vitro functional studies of p.R155H demonstrate a mild functional effect and is associated with mild HPA (Himmelreich et al., 2018; Dobrowolski et al., 2009); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Responsiveness to BH4 is unknown (Trunzo et al., 2015); This variant is associated with the following publications: (PMID: 32668217, 30275481, 31980526, 30747360, 26210745, 21147011, 23932990, 29499199, 30037505, 27264808, 18937047, 9634518, 24401910, 28754886)
Fulgent Genetics, Fulgent Genetics	RCV000632881	SCV002813981	pathogenic	Phenylketonuria	2022-05-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000632881	SCV004209632	pathogenic	Phenylketonuria	2024-03-07	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000632881	SCV004804991	pathogenic	Phenylketonuria	2024-03-17	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000632881	SCV004848750	pathogenic	Phenylketonuria	2022-08-26	criteria provided, single submitter	clinical testing	The p.Arg155His variant in PAH has been reported in at least 19 individuals with phenylalanine hydroxylase deficiency/phenylketonuria (PKU)/hyperphenylalaninemia (HPA) (Trunzo 2015 PMID: 26210745, Liang 2014 PMID: 24401910, Zhu 2013 PMID: 23932990, Guldberg 1998 PMID: 9634518, and Cinar 2022 PMID: 35355500), including 4 siblings in one family and members of 5 additional families (Dabrowolski SF 2011 PMID: 21147011, Dabrowolski 2009 PMID: 18937047). All of these individuals were compound heterozygous for a second pathogenic PAH variant. It has been identified in 0.0003% of ASJ chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as pathogenic on 01/20/20 by the ClinGen PAH Variant Curation Expert Panel (Variation ID: 102686). Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to to determine pathogenecity. In vitro functional studies support an impact of p.Arg155His on protein function, although the degree of impact is debated (21% and 55% reduced activity as compared to wildtype, respectively) (Himmelreich 2018 PMID: 30037505, Dabrowolski 2008 PMID: 18937047). This variant occurs in exon 5 of PAH where numerous pathogenic variants in PAH have been identified, including at the same residue (p.Arg155Cys, p.Arg155Pro). In summary, c.464G>A (p.Arg155His) meets criteria to be classified as pathogenic for autosomal recessive PAH deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PM5_Strong, PM2_Supporting, PP3, PP4, PS3_Supporting.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000632881	SCV005871581	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PP3_Strong+PM3_VeryStrong+PP4_Moderate+PP1_Strong
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088934	SCV000119534	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000632881	SCV001455104	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000632881	SCV004800847	pathogenic	Phenylketonuria		no assertion criteria provided	clinical testing	PM2+PM3_VS+PP3+PP4_M