Submissions for variant NM_000277.3(PAH):c.631C>A (p.Pro211Thr)

gnomAD frequency: 0.00003  dbSNP: rs62514931

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000411219	SCV001762305	pathogenic	Phenylketonuria	2020-07-03	reviewed by expert panel	curation	The c.631C>A (p.Pro211Thr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) (PMID: 11708866, 21147011, 1619813). This variant has an extremely low allele frequency (MAF=0.00004) in gnomAD. It was detected with multiple pathogenic variants: IVS10-11G>A (4 patients, PMID: 21147011); p.R261Q in 2 unrelated patients (PMID: 11708866); p.R408W (PMID: 9429153); p.G272X (PMID: 16198137). Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3.
Counsyl	RCV000411219	SCV000485613	likely pathogenic	Phenylketonuria	2016-01-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411219	SCV000947663	pathogenic	Phenylketonuria	2024-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 211 of the PAH protein (p.Pro211Thr). This variant is present in population databases (rs62514931, gnomAD 0.004%). This missense change has been observed in individuals with PAH-related conditions (PMID: 8268925, 9429153, 11708866, 16198137, 17935162, 23500595). ClinVar contains an entry for this variant (Variation ID: 102766). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 11708866, 21953985). This variant disrupts the p.Pro211 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24350308; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192748	SCV001361069	pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2021-09-11	criteria provided, single submitter	clinical testing	Variant summary: PAH c.631C>A (p.Pro211Thr) results in a non-conservative amino acid change located in the catalytic domain (IPR041912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251336 control chromosomes (gnomAD). c.631C>A has been reported in the literature in multiple individuals (both homozygous and compound heterozygous state) affected with Hyperphenylalaninemia (Guldberg_1993, Couce_2013, Hennermann_2005). These data indicate that the variant is very likely to be associated with disease. Many reports indicate that patients harboring this variant are responsive to tetrahydrobiopterin (BH4) therapy. Anjema_2013 associates this variant with true BH4 responsiveness. Several publications report experimental evidence evaluating an impact on protein function. In most of these functional experiments, variant of interest had a mild reduction in activity compared to the wild type and therefore suggests a subtle effect on protein function. An in vitro assay found this variant to retain 72% of residual activity (Mirisola_2001). Scheller_2019 documented that this variant retains its ability to associate with wild-type PAH, does not form aggregates, and only mildly destabilized in structure. Using sequence conversion and stability methods, Shi_ 2012 suggests a low impact for this variant on protein function. Multiple clinical diagnostic laboratories and an expert panel (ClinGen PAH Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000089016	SCV001804905	pathogenic	not provided	2019-07-10	criteria provided, single submitter	clinical testing	Reported in multiple individuals with mild phenylketonuria (PKU) and mild hyperphenylalaninemia (HPA), in both the homozygous state and in the presence of a second pathogenic variant (Couce et al., 2012; Polak et al., 2013; Hennermann et al., 2005; Mirisola et al., 2001); 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; This variant is associated with the following publications: (PMID: 30648773, 11708866, 16051511, 23764561, 23430859, 17935162, 21953985, 8268925, 26666653, 8830172, 23500595)
Genome-Nilou Lab	RCV000411219	SCV001810552	pathogenic	Phenylketonuria	2021-07-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000411219	SCV004209666	pathogenic	Phenylketonuria	2024-02-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000089016	SCV005051607	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	PAH: PM3:Very Strong, PM2, PM5, PS3:Supporting
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089016	SCV000119620	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000411219	SCV002088655	pathogenic	Phenylketonuria	2020-08-21	no assertion criteria provided	clinical testing