Submissions for variant NM_000277.3(PAH):c.1139C>T (p.Thr380Met) (rs62642937)

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000150077	SCV000852140	pathogenic	Phenylketonuria	2018-10-01	reviewed by expert panel	curation	The c.1139C>T (p.Thr380Met) variant in PAH has been reported in 1 patient with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925). This variant has 28% enzyme activity (PS3; PMID: 27620137). This variant was detected in trans with multiple known pathogenic variants: R408W, R261Q, I65T, F299C (PM3_Very-strong; PMID: 7981714). Computational prediction tools and conservation analysis suggest that the c.1139C>T 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, PS3, PM3_Very-strong
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000078502	SCV000110358	pathogenic	not provided	2016-08-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000078502	SCV000239086	pathogenic	not provided	2019-12-30	criteria provided, single submitter	clinical testing	Functional analysis demonstrates that T380M is associated with 38% of wildtype PAH enzyme activity (Heintz et al., 2012); This variant is associated with the following publications: (PMID: 26990548, 23500595, 23792259, 31355225, 12655544, 17935162, 25087612, 25333069, 8268925, 27620137, 22698810, 30337205, 30747360, 29731766, 31980526, 30275481, 31589614, 32668217)
Illumina Clinical Services Laboratory,Illumina	RCV000150077	SCV000375562	pathogenic	Phenylketonuria	2017-04-27	criteria provided, single submitter	clinical testing	The PAH c.1139C>T (p.Thr380Met) missense variant has been reported in at least 14 studies in which it is found in a total of 24 patients with phenylalanine hydroxylase deficiency including in 19 in a compound heterozygous state, and five in a heterozygous state (Guldberg et al. 1993; Zschocke et al. 1994; Zschocke et al. 1995; Kayaalp et al. 1997; Zekanowski et al. 1997; Pérez et al. 1997; Tyfield et al. 1997; Guldberg et al. 1998; Yang et al. 2001; Ho et al. 2014; Liu et al 2015). The p.Thr380Met variant was found in 1.2 - 5% of alleles tested in subsequent studies of PAH deficiency (Desviat et al. 1999; Bercovich et al. 2008; Okano et al. 2011). Control data are unavailable for this variant from these studies, which is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. In functional studies by Heintz et al. (2012), the p.Thr380Met variant enzyme was shown to have a reduced activity of 38% compared to the wild type. This residual activity is consistent with the milder phenotype associated with this variant. The variant created a new exonic splice enhancer resulting in a stronger definition of exon 11 of the PAH gene, having a positive effect on splicing and the inclusion of exon 11. RNA affinity binding and Western blotting analysis showed that the p.Thr380Met variant abolished the normal binding of three splicing factors seen in the wild type. When found with a severe PAH variant, the p.Thr380Met variant is thought be involved in mild elevations of serum phenylalanine. These patients do not require dietary treatment. Based on the collective evidence, the p.Thr380Met 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078502	SCV000601707	pathogenic	not provided	2017-06-06	criteria provided, single submitter	clinical testing
Invitae	RCV000150077	SCV000629172	pathogenic	Phenylketonuria	2020-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 380 of the PAH protein (p.Thr380Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs62642937, ExAC 0.05%). This variant has been reported in the literature in the homozygous and in the heterozygous state in multiple individuals affected with mild phenylketonuria (PKU) or mild hyperphenylalaninemia (HPA) (PMID: 8268925, 23500595, 18299955, 14722928, 26666653, 10598814, 26600521, 9429153, 8533759, Invitae). ClinVar contains an entry for this variant (Variation ID: 628). Experimental studies have shown that this missense change disrupts PAH protein function decreasing the residual enzymatic activity to 28-38% of wild-type in vitro (PMID: 22698810, 27620137). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280537	SCV000696427	pathogenic	BH4-deficient hyperphenylalaninemia A	2020-12-02	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1139C>T (p.Thr380Met) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal 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 0.00044 in 251264 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Hyperphenylalaninemia (0.00044 vs 0.0079), allowing no conclusion about variant significance. c.1139C>T has been reported in the literature in multiple individuals affected with Hyperphenylalaninemia (example, Ho_2013, Zschocke_1995, Bercovich_2008, Guldberg_1998, Heintz_2012, Zekanowski_1997). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Heintz_2012). The most pronounced variant effect results in 30%-50% of normal PAH activity. Multiple clinical diagnostic laboratories and one expert panel (ClinGen PAH Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000150077	SCV000744092	pathogenic	Phenylketonuria	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000150077	SCV000745570	likely pathogenic	Phenylketonuria	2016-07-26	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000150077	SCV000893267	pathogenic	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000150077	SCV000966190	pathogenic	Phenylketonuria	2018-10-17	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000850463	SCV000992661	uncertain significance	Marfanoid habitus and intellectual disability		criteria provided, single submitter	research
Baylor Genetics	RCV000150077	SCV001163714	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing
Myriad Women's Health, Inc.	RCV000150077	SCV001193784	likely pathogenic	Phenylketonuria	2019-12-20	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.1139C>T(T380M) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 27620137, 22698810, 8830172, 10598814, 17096675, 23792259, 9012412, 10394930, 26666653, 27243974, 8533759, 26542770, 23357515, 12655553, 16198137, 9298832, 27121329, 14722928, 18294361, 18299955, 23500595, 8268925, 21307867, 9634518, 23932990, 10693064, 16198137, 8533759, 11385716, 22698810, 24350308, 17924342, 21147011 and 24368688. Classification of NM_000277.1(PAH):c.1139C>T(T380M) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute	RCV000150077	SCV001245020	pathogenic	Phenylketonuria	2018-10-12	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_000277.1(PAH):c.1139C>T, has been identified in exon 11 of 13 of the PAH gene. The variant is predicted to result in a moderate amino acid change from a threonine to a methionine at position 380 of the protein, NP_000268.1(PAH):p.(Thr380Met). The threonine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the biopterin domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.04% (108 heterozygotes, 1 homozygote). The variant has previously been described multiple times as pathogenic in patients with phenylalanine hydroxylase deficiency (ClinVar). Additionally, patients with this variants were shown to have a reduced enzyme activity of 38% (Heintz, C., et al. (2012)). Analysis of parental samples indicated this variant was paternally inherited and to be present in cis with the second reported PAH variant. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Genomic Research Center,Shahid Beheshti University of Medical Sciences	RCV000150077	SCV001251673	likely pathogenic	Phenylketonuria	2020-05-03	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000078502	SCV001501014	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Nilou-Genome Lab	RCV000150077	SCV001810547	pathogenic	Phenylketonuria	2021-07-22	criteria provided, single submitter	clinical testing
OMIM	RCV000000660	SCV000020810	pathogenic	Hyperphenylalaninemia, non-pku	1994-01-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078502	SCV000119353	not provided	not provided		no assertion provided	not provided
Division of Human Genetics,Children's Hospital of Philadelphia	RCV000150077	SCV000536867	pathogenic	Phenylketonuria	2016-05-19	no assertion criteria provided	research
Natera, Inc.	RCV000150077	SCV001463119	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000150077	SCV001552997	pathogenic	Phenylketonuria		no assertion criteria provided	clinical testing	The PAH c.1139C>T (p.Thr380Met) missense variant has been reported in at least 14 studies in which it is found in a total of 24 patients with phenylalanine hydroxylase deficiency including in 19 in a compound heterozygous state, and five in a heterozygous state (Guldberg et al. 1993; Zschocke et al. 1994; Zschocke et al. 1995; Kayaalp et al. 1997; Zekanowski et al. 1997; Pérez et al. 1997; Tyfield et al. 1997; Guldberg et al. 1998; Yang et al. 2001; Ho et al. 2014; Liu et al 2015). The p.Thr380Met variant was found in 1.2 - 5% of alleles tested in subsequent studies of PAH deficiency (Desviat et al. 1999; Bercovich et al. 2008; Okano et al. 2011). Control data are unavailable for this variant from these studies, which is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. In functional studies by Heintz et al. (2012), the p.Thr380Met variant enzyme was shown to have a reduced activity of 38% compared to the wild type. This residual activity is consistent with the milder phenotype associated with this variant. The variant created a new exonic splice enhancer resulting in a stronger definition of exon 11 of the PAH gene, having a positive effect on splicing and the inclusion of exon 11. RNA affinity binding and Western blotting analysis showed that the p.Thr380Met variant abolished the normal binding of three splicing factors seen in the wild type. When found with a severe PAH variant, the p.Thr380Met variant is thought be involved in mild elevations of serum phenylalanine. These patients do not require dietary treatment. The variant was identified in dbSNP (rs62642937) and ClinVar (classified as pathogenic by multiple sources) databases. The variant was identified in control databases in 181 of 282,648 alleles (1 homozygous) at a frequency of 0.04%, and was observed at the highest frequency in the Ashkenazi Jewish population in 10,364 of 282,648 alleles (freq: 0.47%) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Thr380Met residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. Based on the collective evidence, the p.Thr380Met variant is classified as pathogenic for phenylalanine hydroxylase deficiency.¬â€
Human Genetics - Radboudumc,Radboudumc	RCV000078502	SCV001958930	likely pathogenic	not provided		no assertion criteria provided	clinical testing