NM_000277.3(PAH):c.691T>C (p.Ser231Pro) AND Phenylketonuria

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Mar 8, 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:: RCV000190611.14

Allele description [Variation Report for NM_000277.3(PAH):c.691T>C (p.Ser231Pro)]

NM_000277.3(PAH):c.691T>C (p.Ser231Pro)

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.691T>C (p.Ser231Pro)

HGVS:

NC_000012.12:g.102855151A>G
NG_008690.2:g.108260T>C
NM_000277.3:c.691T>CMANE SELECT
NM_001354304.2:c.691T>C
NP_000268.1:p.Ser231Pro
NP_001341233.1:p.Ser231Pro
NC_000012.11:g.103248929A>G
NM_000277.1:c.691T>C
P00439:p.Ser231Pro

Protein change:

S231P

Links:

UniProtKB: P00439#VAR_000939; dbSNP: rs5030845

NCBI 1000 Genomes Browser:

rs5030845

Molecular consequence:

NM_000277.3:c.691T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.691T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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PKD2 [Pelodiscus sinensis]
PKD2 [Pelodiscus sinensis]
Gene ID:102448832

Gene
DPL1 dihydrosphingosine phosphate lyase [Arabidopsis thaliana]
DPL1 dihydrosphingosine phosphate lyase [Arabidopsis thaliana]
Gene ID:839691

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000245645	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq	criteria provided, single submitter (LMM Criteria)	Pathogenic (Sep 24, 2014)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24301756, 8535444, 22763404, 10196714, 18346471, 24033266
SCV000796824	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Jan 3, 2018)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 8535444, 23842451, 24301756, 10527663, 23430918, 17096675, 10196714, 22763404 Citation Link,
SCV001223743	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8535444, 10394930, 18346471, 27682710, 28492532
SCV001453116	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002015118	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 29, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004201386	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 8, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
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

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype.

Anjema K, van Rijn M, Hofstede FC, Bosch AM, Hollak CE, Rubio-Gozalbo E, de Vries MC, Janssen MC, Boelen CC, Burgerhof JG, Blau N, Heiner-Fokkema MR, van Spronsen FJ.

Orphanet J Rare Dis. 2013 Jul 10;8:103. doi: 10.1186/1750-1172-8-103.

PubMed [citation]

PMID:: 23842451
PMCID:: PMC3711849

See all PubMed Citations (15)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq, SCV000245645.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Ser231Pro variant has been reported at least seven individuals with phenylketonuria (PKU) in the homozygous or compound heterozygous state (Effat 1999, Daniele 2008, Hamzelhoei 2012, Ajami 2013), and was not identified in large population studies. In vitro functional assays suggest complete loss of enzymatic activity (Dianzani 1995). In summary, this variant meets our criteria to be classified as pathogenic for PKU in an autosomal recessive manner for PKU based upon presence in affected individuals, absence from controls, and functional evidence (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medicine/).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Counsyl, SCV000796824.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	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, SCV001223743.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PAH function (PMID: 8535444, 10394930). 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: 102786). This missense change has been observed in individual(s) with phenylketonuria (PMID: 18346471, 27682710). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 231 of the PAH protein (p.Ser231Pro).

#	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., SCV001453116.1

#	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, SCV002015118.1

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

Description

Variant summary: PAH c.691T>C (p.Ser231Pro) results in a non-conservative amino acid change in 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 251314 control chromosomes. c.691T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, e.g. Shirzadeh_2018). These data indicate that the variant is very likely to be associated with disease. Three 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, SCV004201386.2

#	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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