NM_000277.3(PAH):c.733G>C (p.Val245Leu) AND Phenylketonuria

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jun 26, 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:: RCV000340479.13

Allele description [Variation Report for NM_000277.3(PAH):c.733G>C (p.Val245Leu)]

NM_000277.3(PAH):c.733G>C (p.Val245Leu)

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.733G>C (p.Val245Leu)

Other names:

NM_000277.2(PAH):c.733G>C

HGVS:

NC_000012.12:g.102852924C>G
NG_008690.2:g.110487G>C
NM_000277.3:c.733G>CMANE SELECT
NM_001354304.2:c.733G>C
NP_000268.1:p.Val245Leu
NP_001341233.1:p.Val245Leu
NC_000012.11:g.103246702C>G
NM_000277.1:c.733G>C
P00439:p.Val245Leu

Protein change:

V245L

Links:

UniProtKB: P00439#VAR_000951; dbSNP: rs62508694

NCBI 1000 Genomes Browser:

rs62508694

Molecular consequence:

NM_000277.3:c.733G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.733G>C - 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
SCV000797092	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jan 19, 2018)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17924342, 11161839, 22841515, 9012412, 8659548, 24667082, 24368688 Citation Link,
SCV001213578	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 14, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 8659548, 22841515, 24368688, 24667082, 11161839, 17924342, 8088845, 24296287, 25596310, 26803807, 28492532
SCV001363420	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 3, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24368688, 22841515, 8659548, 11161839, 9012412, 24667082 Citation Link,
SCV004015306	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Jun 26, 2020)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 24368688, 8659548, 11161839 Citation Link,
SCV004209655	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 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

Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases.

Pey AL, Stricher F, Serrano L, Martinez A.

Am J Hum Genet. 2007 Nov;81(5):1006-24. Epub 2007 Oct 2.

PubMed [citation]

PMID:: 17924342
PMCID:: PMC2265664

Molecular heterogeneity of nonphenylketonuria hyperphenylalaninemia in 25 Danish patients.

Guldberg P, Henriksen KF, Thöny B, Blau N, Güttler F.

Genomics. 1994 May 15;21(2):453-5. No abstract available.

PubMed [citation]

PMID:: 8088845

See all PubMed Citations (13)

Details of each submission

From Counsyl, SCV000797092.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001213578.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 245 of the PAH protein (p.Val245Leu). This variant is present in population databases (rs62508694, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 8659548, 22841515, 24368688, 24667082). ClinVar contains an entry for this variant (Variation ID: 102810). 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. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839, 17924342). This variant disrupts the p.Val245 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8088845, 24296287, 25596310, 26803807). 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, SCV001363420.2

#	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.733G>C (p.Val245Leu) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251200 control chromosomes. c.733G>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Guldberg_1996, Quirk_2012, Tyfield_1997, Ho_2014, Grange_2014). 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. The most pronounced variant effect results in 10%-<30% of normal PAH enzyme activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was 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 ClinGen PAH Variant Curation Expert Panel, SCV004015306.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

The c.733G>C (p.Val245Leu) variant in PAH has been reported in 3 individuals with PAH deficiency, detected with pathogenic variants p.R408Q and p.A104D (PMID: 8659548, 24368688). This variant has an extremely low allele frequency (0.000008972) in gnomAD. This variant has 13% enzyme activity (PMID: 11161839). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PS3, PM2, PM3, PP3.

#	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, SCV004209655.2

#	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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