Submissions for variant NM_000277.3(PAH):c.299A>G (p.His100Arg)

gnomAD frequency: 0.00035  dbSNP: rs148393887

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000370322	SCV000852112	uncertain significance	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: BP4: In silico overwhelmingly predict benign. REVEL = 0.553; PP4: Detected in a patient with non PKU hyperphe (PMID:11244681); PM3: H100R detected with IVS10 (PMID:11244681). 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: (BP4, PP4, PM3).
Illumina Laboratory Services, Illumina	RCV000370322	SCV000375570	uncertain significance	Phenylketonuria	2017-04-27	criteria provided, single submitter	clinical testing	The PAH c.299A>G (p.His100Arg) missense variant has been reported in one individual in a compound heterozygous state with a known pathogenic intronic variant (Mallolas et al. 1999). The individual was described as having non-phenylketonuria hyperphenylalaninemia, which is included in the PAH deficiency spectrum. Control data are unavailable for the p.His100Arg variant, which is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. Based on the limited evidence, the p.His100Arg variant is classified as a variant of unknown significance, but suspicious for pathogenicity for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl	RCV000370322	SCV000791580	uncertain significance	Phenylketonuria	2017-05-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000370322	SCV000896234	uncertain significance	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000370322	SCV001414935	uncertain significance	Phenylketonuria	2022-08-18	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 100 of the PAH protein (p.His100Arg). This variant is present in population databases (rs148393887, gnomAD 0.05%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 11244681). ClinVar contains an entry for this variant (Variation ID: 306914). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290651	SCV001478778	uncertain significance	not specified	2021-01-11	criteria provided, single submitter	clinical testing	Variant summary: PAH c.299A>G (p.His100Arg) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 251456 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00031 vs 0.0079), allowing no conclusion about variant significance. c.299A>G has been reported in the literature in at least an individual affected with non PKU HPA (Mallolas_1999). This report however, does not provide unequivocal conclusions about association of the variant with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) including an expert panel (ClinGen PAH Variant Curation Expert Panel) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002272209	SCV002558239	uncertain significance	not provided	2022-01-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 30311390, 11244681, 32668217, 10598814)
Ambry Genetics	RCV002520783	SCV003613015	uncertain significance	Inborn genetic diseases	2022-07-08	criteria provided, single submitter	clinical testing	The c.299A>G (p.H100R) alteration is located in exon 3 (coding exon 3) of the PAH gene. This alteration results from a A to G substitution at nucleotide position 299, causing the histidine (H) at amino acid position 100 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000370322	SCV003816613	uncertain significance	Phenylketonuria	2021-10-19	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000370322	SCV001551720	uncertain significance	Phenylketonuria		no assertion criteria provided	clinical testing	The PAH c.299A>G (p.His100Arg) variant was identified in ClinVar (classified as a VUS by multiple sources) and dbSNP (rs148393887). The PAH c.299A>G (p.His100Arg) missense variant has been reported in one individual in a compound heterozygous state with a known pathogenic intronic variant (Mallolas et al. 1999). The individual was described as having non-phenylketonuria hyperphenylalaninemia, which is included in the PAH deficiency spectrum. The variant was identified in control databases in 83 of 282, 858 chromosomes (0 homozygous) at a frequency of 0.0293%, and was observed at the highest frequency in the European Non-Finnish population in 129,164 of 282, 858 chromosomes (freq: 0.0503%) (Genome Aggregation Database March 6, 2019, v2.1.1). The p. His100Arg residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.PAH is associated with autosomal recessive Phenylketonuria (PKU) and non-PKU mild hyperphenylalaninemia (Phenotype MIM number: 261600). PKU is an inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH), an enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism. If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (Zurfluh et al., 2008).
Natera, Inc.	RCV000370322	SCV002088670	uncertain significance	Phenylketonuria	2020-01-17	no assertion criteria provided	clinical testing