NM_000277.3(PAH):c.1033G>T (p.Ala345Ser) AND Phenylketonuria

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jun 5, 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:: RCV000586982.12

Allele description

NM_000277.3(PAH):c.1033G>T (p.Ala345Ser)

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.1033G>T (p.Ala345Ser)

Other names:

p.A345S:GCT>TCT

HGVS:

NC_000012.12:g.102844368C>A
NG_008690.2:g.119043G>T
NM_000277.3:c.1033G>TMANE SELECT
NM_001354304.2:c.1033G>T
NP_000268.1:p.Ala345Ser
NP_001341233.1:p.Ala345Ser
NC_000012.11:g.103238146C>A
NM_000277.1:c.1033G>T
NM_000277.2(PAH):c.1033G>T
P00439:p.Ala345Ser

Protein change:

A345S

Links:

UniProtKB: P00439#VAR_001009; dbSNP: rs62516062

NCBI 1000 Genomes Browser:

rs62516062

Molecular consequence:

NM_000277.3:c.1033G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.1033G>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
SCV000696422	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23430918, 17502162, 24368688, 14654665 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000789292	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jan 17, 2017)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17502162, 14654665, 17924342, 12173030, 23430918, 24368688 Citation Link,
SCV000893269	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001235796	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17502162, 23430918, 24368688, 28492532
SCV001463125	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001762344	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Jun 5, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004209569	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 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

Citations

PubMed

Structural studies on phenylalanine hydroxylase and implications toward understanding and treating phenylketonuria.

Erlandsen H, Patch MG, Gamez A, Straub M, Stevens RC.

Pediatrics. 2003 Dec;112(6 Pt 2):1557-65. Review.

PubMed [citation]

PMID:: 14654665

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 (8)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696422.1

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

Description

Variant summary: The PAH c.1033G>T (p.Ala345Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the C-terminal aromatic amino acid hydroxylase domain (InterPro) and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000166 (2/120330 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Published studies have identified the variant in numerous with patients with PKU and/or HPA, including reports of this variant in compound heterozygosity with other pathogenic/likely pathogenic variants and evidence that the variant cosegregates with disease in a family (Ho_JIMDReports_2013). Additionally, one publication that analyzed the crystal structure of PAH protein reported that the variant of interest is one of "three residues in the active site that are located near the (putative) location of substrate binding or in the region near the catalytic iron" sites, suggesting the variant likely disrupts the critical functions of the protein (Erlandsen_Pediatrics_2003). There are no published in vitro functional studies for the variant; however calculation of the energetic impact (G) by structural modeling shows that this variant leads to lower impact on PAH stability and predicted to cause mild hyperphenylalaninemia (Pey_2007). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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 Counsyl, SCV000789292.1

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

#	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 Fulgent Genetics, Fulgent Genetics, SCV000893269.1

#	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

From Invitae, SCV001235796.5

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 345 of the PAH protein (p.Ala345Ser). This variant is present in population databases (rs62516062, gnomAD 0.008%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 17502162, 23430918, 24368688). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102484). 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., SCV001463125.1

#	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 ClinGen PAH Variant Curation Expert Panel, SCV001762344.1

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

Description

The c.1033G>T (p.Ala345Ser) variant in PAH has been reported in multiple individuals with PAH deficiency. (PMID: 24368688, 17502162, 3430918). This variant has an extremely low allele frequency (MAF=0.00008) in gnomAD. It was detected with multiple pathogenic variants: p.R408W (in trans, PMID: 24368688); c.1045T>C, c.194T>C (PMID: 17502162); p.F39del, c.47_48delCT (aka c.43_44CT), c.1066-11G>A (PMID: 23430918); p.E280K, p.L348V, p.Y414C (PMID: 31623983). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP3, PP4.

#	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, SCV004209569.2

#	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 16, 2024

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