NM_000277.3(PAH):c.1033G>T (p.Ala345Ser) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jun 18, 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:: RCV000088715.11

Allele description [Variation Report for NM_000277.3(PAH):c.1033G>T (p.Ala345Ser)]

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000119295	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	no classification provided	not provided	not provided	not provided
SCV000239081	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 18, 2024)	germline	clinical testing	Citation Link,
SCV000281653	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 4, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004222237	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Oct 21, 2022)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 24368688, 23430918, 17502162, 14654665, 12173030, 32778825, 32668217, 8825928, 26467025

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Summary from all submissions

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

Citations

PubMed

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; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness.

Ho G, Alexander I, Bhattacharya K, Dennison B, Ellaway C, Thompson S, Wilcken B, Christodoulou J.

JIMD Rep. 2014;14:55-65. doi: 10.1007/8904_2013_284. Epub 2013 Dec 25.

PubMed [citation]

PMID:: 24368688
PMCID:: PMC4213336

See all PubMed Citations (10)

Details of each submission

From DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE, SCV000119295.1

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

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

From GeneDx, SCV000239081.16

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

Description

Responsive to tetrahydrobiopterin (BH4) therapy is unclear (PMID: 23430918); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24368688, 25525159, 14654665, 3430918, 17502162, 31623983, 32778825, 32668217, 23430918)

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

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000281653.2

#	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	germline	not provided	not provided	not provided	not provided		not provided	0.000069	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004222237.1

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

Description

The frequency of this variant in the general population, 0.000023 (3/129068 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant is associated with a variable phenotype that ranges from non-PKU hyperphenylalaninemia to classic PKU (PMIDs: 32668217 (2020), 24368688 (2014), 23430918 (2012), 17502162 (2007), and 12173030 (2002)). In addition, this variant has been observed in individuals with reported PAH deficiency (PMID: 24368688 (2014) and 17502162 (2007)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

#	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: Oct 13, 2024

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