Submissions for variant NM_000277.3(PAH):c.638T>C (p.Leu213Pro)

dbSNP: rs62516109

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000150086	SCV000852093	pathogenic	Phenylketonuria	2018-10-01	reviewed by expert panel	curation	The c.638T>C (p.Leu213Pro) variant in PAH has been reported in in 4 patients with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8659548; PMID: 19292873; PMID: 21147011). This variant is absent from large population studies (PM2; http://exac.broadinstitute.org). This variant was detected in trans with c.1066-11G>A, E390G, D415N, R261X.(Pathogenic in ClinVar) (PM3_Very-strong; PMID: 19292873; PMID: 21147011; PMID: 8632937). Computational prediction tools and conservation analysis suggest that the c.638T>C variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong
Eurofins Ntd Llc (ga)	RCV000078527	SCV000110383	pathogenic	not provided	2012-08-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000150086	SCV000220516	likely pathogenic	Phenylketonuria	2014-07-18	criteria provided, single submitter	literature only
GeneDx	RCV000078527	SCV000239064	pathogenic	not provided	2023-08-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Tetrahydrobiopterin (BH4) responsiveness is inconsistent (Sarkissian et al., 2012; Djordjevic et al., 2013); This variant is associated with the following publications: (PMID: 9521426, 22112818, 23764561, 25750018, 23430918, 8659548, 23430547, 26666653, 19292873, 32668217, 35405047)
Illumina Laboratory Services, Illumina	RCV000150086	SCV000915572	pathogenic	Phenylketonuria	2018-08-14	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the PAH c.638T>C (p.Leu213Pro) missense variant has been reported in seven individuals with phenylalanine hydroxylase (PAH) deficiency, including in six who carried the variant in a compound heterozygous state with a second variant and in one who was heterozygous for the variant with no second identified variant (Guldberg et al. 1996; Tyfield et al. 1997; Bosco et al. 1998; Daniele et al. 2009; Utz et al. 2012; Djordjevic et al. 2012; Polak et al. 2013). Of the compound heterozygotes, five presented with a classic phenylketonuria (PKU) phenotype, while the remaining compound heterozygote and the heterozygote both presented a mild hyperphenylalaninemia phenotype. Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the collective evidence, the p.Leu213Pro variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV000078527	SCV001249186	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000150086	SCV001390886	pathogenic	Phenylketonuria	2024-04-16	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 213 of the PAH protein (p.Leu213Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 8632937, 9521426, 19292873, 22112818, 23430547). ClinVar contains an entry for this variant (Variation ID: 92747). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150086	SCV001983446	pathogenic	Phenylketonuria	2021-09-23	criteria provided, single submitter	clinical testing	Variant summary: PAH c.638T>C (p.Leu213Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251336 control chromosomes. c.638T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) in the homozygous and compound heterozygous state (Koch_1997, Sarkissian_2011, Jeannesson-Thivisol_2015, Shirzadeh_2018, etc). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000150086	SCV004209689	pathogenic	Phenylketonuria	2024-01-27	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078527	SCV000119623	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000150086	SCV001453117	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing