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

gnomAD frequency: 0.00036  dbSNP: rs62642937

Total submissions: 33

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
Eurofins Ntd Llc (ga)	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 Laboratory Services, 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	2021-06-14	criteria provided, single submitter	clinical testing	This variant is associated with mild hyperphenylalaninemia when present with any other disease-causing variant in the PAH gene (PMIDs: 7981714 (1994), 8533759 (1995), 8268925 (1993), 18294361 (2008), 23500595 (2013), 26600521 (2015), 27121329 (2016), 33803550 (2021)), and is present in a significant percentage of individuals with PAH deficiency (PMIDs: 10234516 (1999), 21307867 (2011), and 27121329 (2016)). Additionally, multiple functional studies have indicated this variant has reduced activity compared to wild type and may affect splicing (PMIDs: 22698810 (2012) and 27620137 (2016)).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000150077	SCV000629172	pathogenic	Phenylketonuria	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 380 of the PAH protein (p.Thr380Met). This variant is present in population databases (rs62642937, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mild phenylketonuria (PKU) or mild hyperphenylalaninemia (HPA) (PMID: 8268925, 8533759, 9429153, 10598814, 14722928, 18299955, 23500595, 26600521, 26666653; internal data). 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: 628). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (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	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	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
Baylor Genetics	RCV000150077	SCV001163714	pathogenic	Phenylketonuria	2024-03-28	criteria provided, single submitter	clinical testing
Myriad Genetics, 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	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (116 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Biopterin H domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as pathogenic by an expert panel in ClinVar. This variant has been observed in multiple compound heterozygote individuals with hyperphenylalaninemia (PMID: 7981714,8268925), as well as a few homozygous or compound heterozygote individuals with phenylketonuria (PMID: 36937954, 24368688). (SP) 1207 - Parental origin of the variant is unresolved (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000150077	SCV001251673	likely pathogenic	Phenylketonuria	2020-05-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000078502	SCV001501014	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000150077	SCV001810547	pathogenic	Phenylketonuria	2021-07-22	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000078502	SCV002009280	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000150077	SCV002016478	pathogenic	Phenylketonuria	2021-03-02	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000150077	SCV002059727	likely pathogenic	Phenylketonuria	2021-07-21	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000150077	SCV002521016	pathogenic	Phenylketonuria	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.042%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27620137). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.99). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 7981714). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV003258654	SCV003983184	pathogenic	Inborn genetic diseases	2023-04-12	criteria provided, single submitter	clinical testing	The c.1139C>T (p.T380M) alteration is located in exon 11 (coding exon 11) of the PAH gene. This alteration results from a C to T substitution at nucleotide position 1139, causing the threonine (T) at amino acid position 380 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.042% (118/282648) total alleles studied. The highest observed frequency was 0.473% (49/10364) of Ashkenazi Jewish alleles. This alteration was detected in the homozygous state and in conjunction with another alteration in PAH in multiple individuals with phenylalanine hydroxylase deficiency (Mart&iacute;n-Rivada, 2022; Odagiri,2021; Ald&aacute;miz-Echevarr&iacute;a, 2016; Bayat, 2016; Bercovich, 2008; Bercovich, 2008; Fiori, 2005; Mallolas, 1999, Zekanowski, 1997). This amino acid position is highly conserved in available vertebrate species. Functional assays show reduced enzyme activity in vitro (Heintz, 2012; Trunzo, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000150077	SCV004807930	likely pathogenic	Phenylketonuria	2024-03-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150077	SCV004848710	pathogenic	Phenylketonuria	2022-06-30	criteria provided, single submitter	clinical testing	The p.Thr380Met variant in PAH has been reported in at least seven individuals with phenylalanine hydroxylase deficiency including six compound heterozygotes of which five have pathogenic variants in trans as classified by the ClinGen PAH Variant Curation Expert Panel (Guldberg 1993 PMID: 8268925, Guo 2018 PMID: 29731766, Zschocke 1994 PMID: 7981714). It has also been identified in 0.52% (18/3472) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar as pathogenic by the ClinGen PAH Variant Curation Expert Panel using the . ACMG-AMP criteria specific for phenylalanine hydroxylase variants (Zastrow 2018 PMID: 30311390) and is curated in the FDA-recognized human genetic variant database (Variation ID 628). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function and decreases PAH activity to 28% (Trunzo 2016 PMID: 27620137); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylalanine hydroxylase deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3, PP3, PP4_Moderate, BS1_Supporting.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000150077	SCV005051914	pathogenic	Phenylketonuria	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000000660	SCV000020810	pathogenic	Hyperphenylalaninemia	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
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000850463	SCV000992661	uncertain significance	Marfanoid habitus and intellectual disability		flagged submission	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€
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078502	SCV001958930	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390629	SCV004110233	pathogenic	PAH-related disorder	2024-03-23	no assertion criteria provided	clinical testing	The PAH c.1139C>T variant is predicted to result in the amino acid substitution p.Thr380Met. This variant has been reported in multiple studies as causative for mild hyperphenylalaninemia (HPA) when in the compound heterozygous state with a second causative PAH variant (e.g., Mallolas et al. 1999. PubMed ID: 10598814; Bercovich et al. 2008. PubMed ID: 18299955; Heintz et al. 2012. PubMed ID: 22698810; Aldámiz-Echevarría et al. 2016. PubMed ID: 27121329). In in vitro expression assays, the p.Thr380Met substitution reduced the activity of the PAH enzyme to ~28-38% of control (Heintz et al. 2012. PubMed ID: 22698810; Trunzo et al. 2016. PubMed ID: 27620137). The p.Thr380Met amino acid substitution has been reported to result in a mutant PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). The c.1139C>T variant has been reported at an allele frequency of 0.46%, including 1 homozygous individual, in an Ashkenazi Jewish population; in other populations, it is observed less frequently (i.e., <0.1%). This variant is classified as pathogenic in the ClinVar database by the ClinGen PAH Variant Curation Expert Panel and multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/628/). In summary, this variant is classified as pathogenic.