NM_000277.3(PAH):c.428A>G (p.Asp143Gly) AND Phenylketonuria

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Feb 12, 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:: RCV001209954.8

Allele description [Variation Report for NM_000277.3(PAH):c.428A>G (p.Asp143Gly)]

NM_000277.3(PAH):c.428A>G (p.Asp143Gly)

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.428A>G (p.Asp143Gly)

HGVS:

NC_000012.12:g.102877475T>C
NG_008690.2:g.85936A>G
NM_000277.3:c.428A>GMANE SELECT
NM_001354304.2:c.428A>G
NP_000268.1:p.Asp143Gly
NP_001341233.1:p.Asp143Gly
NC_000012.11:g.103271253T>C
NM_000277.1:c.428A>G
P00439:p.Asp143Gly

Protein change:

D143G

Links:

UniProtKB: P00439#VAR_000895; dbSNP: rs199475572

NCBI 1000 Genomes Browser:

rs199475572

Molecular consequence:

NM_000277.3:c.428A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.428A>G - 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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Rattus norvegicus ubiquitin-conjugating enzyme E2E 2 (UBC4/5 homolog, yeast), mR...
Rattus norvegicus ubiquitin-conjugating enzyme E2E 2 (UBC4/5 homolog, yeast), mRNA (cDNA clone IMAGE:7127579), partial cds
gi|50925720|gb|BC079134.1|

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Homo sapiens cDNA clone IMAGE:2958041
Homo sapiens cDNA clone IMAGE:2958041
gi|14712195|gb|BC007217.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001381411	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 10, 2019)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21953985, 10980574, 9450897, 8889583, 21147011, 18937047, 28492532
SCV005053828	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 12, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001381411

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 10, 2019)

germline

clinical testing

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

SCV005053828

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 12, 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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase.

Shi Z, Sellers J, Moult J.

Proteins. 2012 Jan;80(1):61-70. doi: 10.1002/prot.23159. Epub 2011 Sep 21.

PubMed [citation]

PMID:: 21953985
PMCID:: PMC4170182

Structural interpretation of mutations in phenylalanine hydroxylase protein aids in identifying genotype-phenotype correlations in phenylketonuria.

Jennings IG, Cotton RG, Kobe B.

Eur J Hum Genet. 2000 Sep;8(9):683-96.

PubMed [citation]

PMID:: 10980574

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001381411.4

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

Description

This variant has been reported to affect PAH protein function (PMID: 8889583, 21953985, 18937047, 10980574, 9450897). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in combination with another PAH variant in individuals affected with PAH-related conditions (PMID: 8889583, 21147011, 18937047, Invitae). ClinVar contains an entry for this variant (Variation ID: 102666). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 143 of the PAH protein (p.Asp143Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine.

#	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, SCV005053828.1

#	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: Sep 29, 2024

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