NM_000277.3(PAH):c.1238G>A (p.Arg413His) AND Phenylketonuria

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Mar 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001210291.9

Allele description [Variation Report for NM_000277.3(PAH):c.1238G>A (p.Arg413His)]

NM_000277.3(PAH):c.1238G>A (p.Arg413His)

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.1238G>A (p.Arg413His)

HGVS:

NC_000012.12:g.102840477C>T
NG_008690.2:g.122934G>A
NM_000277.3:c.1238G>AMANE SELECT
NM_001354304.2:c.1238G>A
NP_000268.1:p.Arg413His
NP_001341233.1:p.Arg413His
NC_000012.11:g.103234255C>T
NM_000277.1:c.1238G>A

Protein change:

R413H

Links:

dbSNP: rs79931499

NCBI 1000 Genomes Browser:

rs79931499

Molecular consequence:

NM_000277.3:c.1238G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.1238G>A - 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
SCV001381770	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30459323, 17935162, 21953985, 24401910, 27264808, 28492532
SCV002051333	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 23, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32668217, 30459323 Citation Link,
SCV004209599	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001381770

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 30, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002051333

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Dec 23, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004209599

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 27, 2024)

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

Citations

PubMed

Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.

Zurflüh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N.

Hum Mutat. 2008 Jan;29(1):167-75.

PubMed [citation]

PMID:: 17935162

Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase.

Shi Z, Sellers J, Moult J.

Proteins. 2012 Jan;80(1):61-70. doi: 10.1002/prot.23159. Epub 2011 Sep 21.

PubMed [citation]

PMID:: 21953985
PMCID:: PMC4170182

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001381770.5

#	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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 413 of the PAH protein (p.Arg413His). This variant is present in population databases (rs79931499, gnomAD 0.03%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 30459323). ClinVar contains an entry for this variant (Variation ID: 940659). 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 with a negative predictive value of 80%. This variant disrupts the p.Arg413 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17935162, 21953985, 24401910, 27264808). 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, SCV002051333.1

#	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.1238G>A (p.Arg413His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251440 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (5.6e-05 vs 0.0079), allowing no conclusion about variant significance. c.1238G>A has been reported in the literature in individuals affected with classic phenylketonuria or mild hyperphenylalaninemia (Chen_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Other variants affecting this codon (R413C, R413G, R413P, R413S) have been reported to associate with Phenylketonuria (HGMD database). 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, SCV004209599.2

#	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: Sep 29, 2024

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