Submissions for variant NM_000277.3(PAH):c.320A>G (p.His107Arg)

gnomAD frequency: 0.00001  dbSNP: rs542645236

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000210807	SCV001572860	pathogenic	Phenylketonuria	2020-12-09	reviewed by expert panel	curation	This c.320A>G (p.His107Arg) variant in PAH was reported in 22 patients with PAH deficiency (>120 uMol/L Phe), detected in trans in 16 patients with pathogenic variants p.Arg111*, p.Arg400Thr, p.Val399=, p.Val399=, p.Arg241Cys, p.Arg241Cys, p.Arg413Pro, p.Gly257Val, p.His107Arg, p.Arg243Gln, p.His220Pro, p.Arg176*, p.Arg243Gln, p.Arg243Gln, p.Val230Ile, p.Ile65Thr (PMID: 28982351). Computational evidence for this variant is conflicting; predicted to be tolerated (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant is present in European (Non-Finnish) populations at extremely low frequencies in gnomAD (MAF=0.00002), ExAC (MAF=0.00001), and 1000 Genomes (MAF=0.00099). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_very-strong, PP4.
Counsyl	RCV000210807	SCV000791589	likely pathogenic	Phenylketonuria	2017-05-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000210807	SCV001163352	pathogenic	Phenylketonuria	2024-03-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000210807	SCV001223781	pathogenic	Phenylketonuria	2024-05-22	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 107 of the PAH protein (p.His107Arg). This variant is present in population databases (rs542645236, gnomAD 0.006%). This missense change has been observed in individual(s) with PAH-related disease (PMID: 21307867, 25456745, 26600521, 29390883, 30050108). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 225134). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000210807	SCV005415805	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM3_VeryStrong+PM2
Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital	RCV000210807	SCV000266851	likely pathogenic	Phenylketonuria	2013-10-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000210807	SCV002088668	pathogenic	Phenylketonuria	2021-01-19	no assertion criteria provided	clinical testing