NM_000277.3(PAH):c.1240T>C (p.Tyr414His) AND Phenylketonuria

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: May 5, 2019
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000106346.10

Allele description [Variation Report for NM_000277.3(PAH):c.1240T>C (p.Tyr414His)]

NM_000277.3(PAH):c.1240T>C (p.Tyr414His)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.1240T>C (p.Tyr414His)

HGVS:

NC_000012.12:g.102840475A>G
NG_008690.2:g.122936T>C
NM_000277.3:c.1240T>CMANE SELECT
NM_001354304.2:c.1240T>C
NP_000268.1:p.Tyr414His
NP_001341233.1:p.Tyr414His
NC_000012.11:g.103234253A>G
NC_000012.11:g.103234253A>G
NM_000277.1:c.1240T>C
NM_000277.2(PAH):c.1240T>C
p.Tyr414His

Protein change:

Y414H

Links:

dbSNP: rs281865437

NCBI 1000 Genomes Browser:

rs281865437

Molecular consequence:

NM_000277.3:c.1240T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.1240T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: FOLLING DISEASE; OLIGOPHRENIA PHENYLPYRUVICA; Phenylketonurias
Identifiers:: MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000143845	Inserm U 954, Faculté de Médecine de Nancy	no assertion criteria provided	Likely pathogenic	unknown	not provided
SCV001250536	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Uncertain significance (May 5, 2019)	germline	curation	Citation Link,
SCV002216693	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 14, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 32668217, 8556304, 9399896, 10479481, 24296287, 28492532 Citation Link,
SCV005075862	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 2, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30648773, 32668217 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	not provided	not provided	not provided	not provided	not provided	2	not provided	literature only

Citations

PubMed

Characterization of phenylketonuria alleles in the Italian population.

Dianzani I, Giannattasio S, de Sanctis L, Alliaudi C, Lattanzio P, Dionisi Vici C, Burlina A, Burroni M, Sebastio G, Carnevale F, et al.

Eur J Hum Genet. 1995;3(5):294-302.

PubMed [citation]

PMID:: 8556304

Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations.

Kayaalp E, Treacy E, Waters PJ, Byck S, Nowacki P, Scriver CR.

Am J Hum Genet. 1997 Dec;61(6):1309-17.

PubMed [citation]

PMID:: 9399896
PMCID:: PMC1716084

See all PubMed Citations (7)

Details of each submission

From Inserm U 954, Faculté de Médecine de Nancy, SCV000143845.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

Description

Converted during submission from probable-pathogenic to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	2	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen PAH Variant Curation Expert Panel, SCV001250536.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.1240T>C (p.Tyr414His) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 125859); the collection method is stated as "literature only" and no further information is provided. To our knowledge, as of 4/29/19, it has not been reported in the published literature. The variant results in the substitution of a highly conserved Tyrosine residue with Histidine, a physiochemically distinct amino acid (nonpolar versus basic side chains), and the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., Predicted deleterious in SIFT, Polyphen2, Mutation Taster. REVEL= 0.969) (PP3). It is present at extremely low frequency in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP: the highest MAF reported is 0.00001, in the gnomAD/ExAC Non-Finnish European subpopulation, which falls below the 0.0002 allele frequency cutoff for PAH variants (PM2). Another missense variant at this site, p.Tyr414Cys, has been previously reported Pathogenic, including by the ClinGen PAH working group (see ClinVar variant ID 593) (PM5).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002216693.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 414 of the PAH protein (p.Tyr414His). This variant is present in population databases (rs281865437, gnomAD 0.0009%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 120265). 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%. This variant disrupts the p.Tyr414 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8556304, 9399896, 10479481, 24296287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005075862.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: PAH c.1240T>C (p.Tyr414His) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. A different pathogenic variant located at the same codon, c.1241A>G (p.Tyr414Cys) supports a critical relevance of this Tyrosine residue to overall PAH protein function. The variant allele was found at a frequency of 4e-06 in 251444 control chromosomes. c.1240T>C has been reported in the literature as a biallelic comound heterozygous genotype in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Hillert_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32668217, 30648773). ClinVar contains an entry for this variant (Variation ID: 120265). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 8, 2025

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