NM_000277.3(PAH):c.1259G>T (p.Arg420Met) AND Phenylketonuria

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: May 21, 2020
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:: RCV001200002.8

Allele description [Variation Report for NM_000277.3(PAH):c.1259G>T (p.Arg420Met)]

NM_000277.3(PAH):c.1259G>T (p.Arg420Met)

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.1259G>T (p.Arg420Met)

HGVS:

NC_000012.12:g.102840456C>A
NG_008690.2:g.122955G>T
NM_000277.3:c.1259G>TMANE SELECT
NM_001354304.2:c.1259G>T
NP_000268.1:p.Arg420Met
NP_001341233.1:p.Arg420Met
NC_000012.11:g.103234234C>A
NC_000012.11:g.103234234C>A
NM_000277.1:c.1259G>T
NM_000277.3:c.1259G>T

Protein change:

R420M

Links:

dbSNP: rs767075719

NCBI 1000 Genomes Browser:

rs767075719

Molecular consequence:

NM_000277.3:c.1259G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.1259G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
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
SCV001370854	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (May 21, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 23500595, 27121329 Citation Link,
SCV002300548	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 9, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23500595, 35281663, 22526846, 28492532
SCV002795475	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003800708	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 30, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23500595, 27243974, 27121329, 32668217, 35281663, 30674554 Citation Link,
SCV004209627	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 31, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Prevalence of tetrahydrobiopterine (BH4)-responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients.

Sterl E, Paul K, Paschke E, Zschocke J, Brunner-Krainz M, Windisch E, Konstantopoulou V, Möslinger D, Karall D, Scholl-Bürgi S, Sperl W, Lagler F, Plecko B.

J Inherit Metab Dis. 2013 Jan;36(1):7-13. doi: 10.1007/s10545-012-9485-y. Epub 2012 Apr 25.

PubMed [citation]

PMID:: 22526846

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (9)

Details of each submission

From ClinGen PAH Variant Curation Expert Panel, SCV001370854.1

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

Description

The c.1259G>T (p.Arg420Met) variant in PAH has been reported in 1 Spanish patient with mild hyperphenylalaninemia (BH4 deficiency excluded) (PP4_Moderate; PMID: 27121329). This variant was detected with p.A403V (Pathogenic in ClinVar, VarID:92731, 18 submitters) (PM3; PMID: 27121329). This variant has a MAF of 0.00002 in population databases (PM2). This variant is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.835 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3, PM3.

#	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 Invitae, SCV002300548.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 420 of the PAH protein (p.Arg420Met). This variant is present in population databases (rs767075719, gnomAD 0.002%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 23500595, 35281663; Invitae). 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: 932268). 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 not expected to disrupt PAH protein function. This variant disrupts the p.Ile421 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22526846). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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

From Fulgent Genetics, Fulgent Genetics, SCV002795475.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	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, SCV003800708.2

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

Description

Variant summary: PAH c.1259G>T (p.Arg420Met) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (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 8e-06 in 251446 control chromosomes. c.1259G>T has been reported in the literature as a heterozygous genotype with a pathogenic variant in individuals (Aldamiz_2016, Martin-Rivada_2022) and in one individual without a specified genotype (Yubero_2016, etc) affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters, including an expert panel, classified the variant as likely pathogenic. 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

From Baylor Genetics, SCV004209627.1

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

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

Last Updated: Feb 14, 2024

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