NM_000277.3(PAH):c.631C>A (p.Pro211Thr) AND Phenylketonuria

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jul 3, 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:: RCV000411219.12

Allele description [Variation Report for NM_000277.3(PAH):c.631C>A (p.Pro211Thr)]

NM_000277.3(PAH):c.631C>A (p.Pro211Thr)

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.631C>A (p.Pro211Thr)

HGVS:

NC_000012.12:g.102855211G>T
NG_008690.2:g.108200C>A
NM_000277.3:c.631C>AMANE SELECT
NM_001354304.2:c.631C>A
NP_000268.1:p.Pro211Thr
NP_001341233.1:p.Pro211Thr
NC_000012.11:g.103248989G>T
NC_000012.11:g.103248989G>T
NM_000277.1(PAH):c.631C>A
NM_000277.1:c.631C>A
P00439:p.Pro211Thr

Protein change:

P211T

Links:

UniProtKB: P00439#VAR_000928; dbSNP: rs62514931

NCBI 1000 Genomes Browser:

rs62514931

Molecular consequence:

NM_000277.3:c.631C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.631C>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
SCV000485613	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jan 13, 2016)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000947663	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 14, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 8268925, 9429153, 16198137, 17935162, 23500595, 11708866, 21953985, 24350308, 28492532
SCV001762305	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Jul 3, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 11708866, 21147011 Citation Link,
SCV001810552	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002088655	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 21, 2020)	germline	clinical testing
SCV004209666	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 24, 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
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe.

Guldberg P, Romano V, Ceratto N, Bosco P, Ciuna M, Indelicato A, Mollica F, Meli C, Giovannini M, Riva E, et al.

Hum Mol Genet. 1993 Oct;2(10):1703-7.

PubMed [citation]

PMID:: 8268925

Molecular basis of mild hyperphenylalaninaemia in Poland.

Zekanowski C, Nowacka M, Cabalska B, Bal J.

J Med Genet. 1997 Dec;34(12):1035-6.

PubMed [citation]

PMID:: 9429153
PMCID:: PMC1051162

See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000485613.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000947663.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 211 of the PAH protein (p.Pro211Thr). This variant is present in population databases (rs62514931, gnomAD 0.004%). This missense change has been observed in individuals with PAH-related conditions (PMID: 8268925, 9429153, 11708866, 16198137, 17935162, 23500595). ClinVar contains an entry for this variant (Variation ID: 102766). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 11708866, 21953985). This variant disrupts the p.Pro211 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24350308; Invitae). 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 ClinGen PAH Variant Curation Expert Panel, SCV001762305.1

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

Description

The c.631C>A (p.Pro211Thr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) (PMID: 11708866, 21147011, 1619813). This variant has an extremely low allele frequency (MAF=0.00004) in gnomAD. It was detected with multiple pathogenic variants: IVS10-11G>A (4 patients, PMID: 21147011); p.R261Q in 2 unrelated patients (PMID: 11708866); p.R408W (PMID: 9429153); p.G272X (PMID: 16198137). Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, 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 Genome-Nilou Lab, SCV001810552.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002088655.1

#	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 Baylor Genetics, SCV004209666.1

#	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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