NM_000277.3(PAH):c.940C>T (p.Pro314Ser) AND Phenylketonuria

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 9, 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:: RCV000758098.5

Allele description [Variation Report for NM_000277.3(PAH):c.940C>T (p.Pro314Ser)]

NM_000277.3(PAH):c.940C>T (p.Pro314Ser)

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.940C>T (p.Pro314Ser)

Other names:

NM_000277.2(PAH):c.940C>T

HGVS:

NC_000012.12:g.102846924G>A
NG_008690.2:g.116487C>T
NM_000277.3:c.940C>TMANE SELECT
NM_001354304.2:c.940C>T
NP_000268.1:p.Pro314Ser
NP_001341233.1:p.Pro314Ser
NC_000012.11:g.103240702G>A
NC_000012.11:g.103240702G>A
NM_000277.1:c.940C>T
P00439:p.Pro314Ser

Protein change:

P314S

Links:

UniProtKB: P00439#VAR_068006; dbSNP: rs199475650

NCBI 1000 Genomes Browser:

rs199475650

Molecular consequence:

NM_000277.3:c.940C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.940C>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
SCV000886568	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Dec 9, 2018)	germline	curation	Citation Link,
SCV002244459	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 24401910, 28982351, 29390883, 18538294, 12501224, 32668217, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000886568

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Pathogenic
(Dec 9, 2018)

germline

curation

Citation Link,

SCV002244459

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2021)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

Citations

PubMed

The mutation spectrum of the phenylalanine hydroxylase (PAH) gene and associated haplotypes reveal ethnic heterogeneity in the Taiwanese population.

Liang Y, Huang MZ, Cheng CY, Chao HK, Fwu VT, Chiang SH, Hsiao KJ, Niu DM, Su TS.

J Hum Genet. 2014 Mar;59(3):145-52. doi: 10.1038/jhg.2013.136. Epub 2014 Jan 9.

PubMed [citation]

PMID:: 24401910

Spectrum of PAH gene variants among a population of Han Chinese patients with phenylketonuria from northern China.

Liu N, Huang Q, Li Q, Zhao D, Li X, Cui L, Bai Y, Feng Y, Kong X.

BMC Med Genet. 2017 Oct 5;18(1):108. doi: 10.1186/s12881-017-0467-7. Erratum in: BMC Med Genet. 2018 Jan 9;19(1):6. doi: 10.1186/s12881-017-0516-2.

PubMed [citation]

PMID:: 28982351
PMCID:: PMC5629770

See all PubMed Citations (7)

Details of each submission

From ClinGen PAH Variant Curation Expert Panel, SCV000886568.2

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

Description

The c.940C>T (p.Pro314Ser) variant in PAH is absent in population databases, and is in the same codon as two previously described Pathogenic/Likely pathogenic variants (p.Pro314His and p.Pro314Thr). It has been found in trans with a pathogenic variant (p.R408W) in a patient with PAH deficiency (BH4 defects excluded, PMID: 12501224). Functional studies showed it has 26% enzyme activity compared to wild type controls. PMID: 18590700. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3, PM5.

#	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, SCV002244459.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro314 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24401910, 28982351, 29390883). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PAH function (PMID: 18538294). 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. ClinVar contains an entry for this variant (Variation ID: 102905). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 12501224, 32668217). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 314 of the PAH protein (p.Pro314Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine.

#	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

Last Updated: Feb 14, 2024

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