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

Total submissions: 16

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
Counsyl	RCV000150077	SCV000221038	likely pathogenic	Phenylketonuria	2015-01-15	criteria provided, single submitter	literature only
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center	RCV000150077	SCV000745570	likely pathogenic	Phenylketonuria	2016-07-26	criteria provided, single submitter	clinical testing
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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000078502	SCV000110358	pathogenic	not provided	2016-08-08	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
Fulgent Genetics,Fulgent Genetics	RCV000150077	SCV000893267	pathogenic	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000078502	SCV000239086	pathogenic	not provided	2018-11-29	criteria provided, single submitter	clinical testing	The T380M missense variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database.
Genome Diagnostics Laboratory,University Medical Center Utrecht	RCV000150077	SCV000744092	pathogenic	Phenylketonuria	2014-10-08	criteria provided, single submitter	clinical testing
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.
Integrated Genetics/Laboratory Corporation of America	RCV000000660	SCV000696427	pathogenic	Hyperphenylalaninemia, non-pku	2016-06-21	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.1139C>T (p.Thr380Met) variant causes a missense change involving a conserved nucleotide and 5/5 in silico tools predicting a "damaging" outcome. This variant lies on active site of catalytic domain, therefore it is expected to alter catalysis. The variant of interest was found in the large and broad control populations from ExAC with an allele frequency of 1/3032 (0.00032; 40/121272 chromosomes), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126 (0.0079057). The variant of interest has been widely reported as a pathogenic mutation that causes mild HPA in the literature. It was found in several affected individuals with mild hyperphenylalaninemia, some patients known to be compound heterozygous with other pathogenic/potentially pathogenic variants. A functional study shows that the variant leads to impaired enzymatic activity consistent with the mild phenotype seen in patients carrying this variant. In addition, multiple reputable clinical laboratories/databases classify the variant as "pathogenic." Taken together, the variant of interest is classified as Pathogenic.
Invitae	RCV000150077	SCV000629172	pathogenic	Phenylketonuria	2018-12-18	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.
OMIM	RCV000000660	SCV000020810	pathogenic	Hyperphenylalaninemia, non-pku	1994-01-01	no assertion criteria provided	literature only
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078502	SCV000601707	pathogenic	not provided	2017-06-06	criteria provided, single submitter	clinical testing