NM_000277.3(PAH):c.638T>C (p.Leu213Pro) AND Phenylketonuria

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Oct 1, 2018
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:: RCV000150086.35

Allele description [Variation Report for NM_000277.3(PAH):c.638T>C (p.Leu213Pro)]

NM_000277.3(PAH):c.638T>C (p.Leu213Pro)

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.638T>C (p.Leu213Pro)

Other names:

p.L213P:CTT>CCT; NM_000277.1(PAH):c.638T>C

HGVS:

NC_000012.12:g.102855204A>G
NG_008690.2:g.108207T>C
NM_000277.3:c.638T>CMANE SELECT
NM_001354304.2:c.638T>C
NP_000268.1:p.Leu213Pro
NP_000268.1:p.Leu213Pro
NP_001341233.1:p.Leu213Pro
NC_000012.11:g.103248982A>G
NM_000277.1:c.638T>C
P00439:p.Leu213Pro

Protein change:

L213P

Links:

UniProtKB: P00439#VAR_000930; dbSNP: rs62516109

NCBI 1000 Genomes Browser:

rs62516109

Molecular consequence:

NM_000277.3:c.638T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.638T>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
SCV000220516	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jul 18, 2014)	unknown	literature only	PubMed (11) [See all records that cite these PMIDs] 19292873, 9521426, 16176881, 23430547, 23764561, 8659548, 8632937, 9012412, 22112818, 17924342, 23430918 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000852093	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Oct 1, 2018)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 8659548, 8632937, 21147011, 19292873 Citation Link,
SCV000915572	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Aug 14, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8659548, 9012412, 9521426, 19292873, 23430547, 22112818, 23764561 Citation Link,
SCV001390886	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 14, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8632937, 9521426, 19292873, 22112818, 23430547, 28492532
SCV001453117	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001983446	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 23, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26666653, 23430918, 9169088, 30159852 Citation Link,
SCV004209689	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 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, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

Inter-individual variation in brain phenylalanine concentration in patients with PKU is not caused by genetic variation in the 4F2hc/LAT1 complex.

Møller LB, Paulsen M, Koch R, Moats R, Guldberg P, Güttler F.

Mol Genet Metab. 2005 Dec;86 Suppl 1:S119-23. Epub 2005 Sep 19.

PubMed [citation]

PMID:: 16176881

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

See all PubMed Citations (17)

Details of each submission

From Counsyl, SCV000220516.2

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

#	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 ClinGen PAH Variant Curation Expert Panel, SCV000852093.4

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

Description

The c.638T>C (p.Leu213Pro) variant in PAH has been reported in in 4 patients with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8659548; PMID: 19292873; PMID: 21147011). This variant is absent from large population studies (PM2; http://exac.broadinstitute.org). This variant was detected in trans with c.1066-11G>A, E390G, D415N, R261X.(Pathogenic in ClinVar) (PM3_Very-strong; PMID: 19292873; PMID: 21147011; PMID: 8632937). Computational prediction tools and conservation analysis suggest that the c.638T>C 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, PM3_Very-strong

#	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 Illumina Laboratory Services, Illumina, SCV000915572.1

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

Description

Across a selection of the available literature, the PAH c.638T>C (p.Leu213Pro) missense variant has been reported in seven individuals with phenylalanine hydroxylase (PAH) deficiency, including in six who carried the variant in a compound heterozygous state with a second variant and in one who was heterozygous for the variant with no second identified variant (Guldberg et al. 1996; Tyfield et al. 1997; Bosco et al. 1998; Daniele et al. 2009; Utz et al. 2012; Djordjevic et al. 2012; Polak et al. 2013). Of the compound heterozygotes, five presented with a classic phenylketonuria (PKU) phenotype, while the remaining compound heterozygote and the heterozygote both presented a mild hyperphenylalaninemia phenotype. Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the collective evidence, the p.Leu213Pro 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.

#	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, SCV001390886.5

#	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 leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 213 of the PAH protein (p.Leu213Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 8632937, 9521426, 19292873, 22112818, 23430547). ClinVar contains an entry for this variant (Variation ID: 92747). 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%. 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 Natera, Inc., SCV001453117.1

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

#	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, SCV001983446.1

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

Description

Variant summary: PAH c.638T>C (p.Leu213Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251336 control chromosomes. c.638T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) in the homozygous and compound heterozygous state (Koch_1997, Sarkissian_2011, Jeannesson-Thivisol_2015, Shirzadeh_2018, etc). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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. 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 Baylor Genetics, SCV004209689.2

#	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: Nov 3, 2024

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