rs62642937

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PP4_ModeratePP3PM3PS3

This summary comes from the ClinGen Evidence Repository: 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 LINK:https://erepo.genome.network/evrepo/ui/classification/CA114369/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

12
5
2

Clinical Significance

Pathogenic reviewed by expert panel P:30U:2O:1

Conservation

PhyloP100: 7.98
Variant links:
Genes affected
PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 9 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAHNM_000277.3 linkc.1139C>T p.Thr380Met missense_variant Exon 11 of 13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkc.1139C>T p.Thr380Met missense_variant Exon 12 of 14 NP_001341233.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkc.1139C>T p.Thr380Met missense_variant Exon 11 of 13 1 NM_000277.3 ENSP00000448059.1 P00439

Frequencies

GnomAD3 genomes
AF:
0.000375
AC:
57
AN:
152082
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.00518
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000442
AC:
111
AN:
251264
Hom.:
1
AF XY:
0.000420
AC XY:
57
AN XY:
135790
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000290
Gnomad ASJ exome
AF:
0.00476
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000396
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000387
AC:
566
AN:
1461372
Hom.:
1
Cov.:
33
AF XY:
0.000373
AC XY:
271
AN XY:
727026
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.000336
Gnomad4 ASJ exome
AF:
0.00478
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000327
Gnomad4 OTH exome
AF:
0.000712
GnomAD4 genome
AF:
0.000375
AC:
57
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.000336
AC XY:
25
AN XY:
74426
show subpopulations
Gnomad4 AFR
AF:
0.0000963
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00518
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000397
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000493
Hom.:
1
Bravo
AF:
0.000366
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.000329
AC:
40
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000654
EpiControl
AF:
0.00107

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:30Uncertain:2Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Phenylketonuria Pathogenic:21
Mar 02, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 29, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 08, 2014
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 21, 2021
Centogene AG - the Rare Disease Company
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 30, 2022
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Jul 22, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 03, 2020
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Jul 26, 2016
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2024
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Oct 01, 2018
ClinGen PAH Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: 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 -

May 22, 2022
3billion
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 17, 2018
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 20, 2019
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

May 19, 2016
Division of Human Genetics, Children's Hospital of Philadelphia
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: 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.  -

Mar 28, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 09, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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 -

not provided Pathogenic:5Uncertain:1Other:1
Jun 14, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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)). -

Dec 30, 2019
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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) -

Aug 08, 2016
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PAH: PM3:Very Strong, PM2, PP4:Moderate, PS3:Moderate -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

PAH-related disorder Pathogenic:1
Mar 23, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: 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. -

Inborn genetic diseases Pathogenic:1
Apr 12, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Hyperphenylalaninemia Pathogenic:1
Jan 01, 1994
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:1
Dec 02, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Marfanoid habitus and intellectual disability Uncertain:1
-
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
1.0
D;D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Pathogenic
4.3
H;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-5.8
D;D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
1.0
D;.
Vest4
0.90
MVP
0.99
MPC
0.24
ClinPred
0.30
T
GERP RS
5.3
Varity_R
0.79
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs62642937; hg19: chr12-103237484; API