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NM_000277.3(PAH):c.136G>A (p.Gly46Ser) AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 7, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002512613.8

Allele description [Variation Report for NM_000277.3(PAH):c.136G>A (p.Gly46Ser)]

NM_000277.3(PAH):c.136G>A (p.Gly46Ser)

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.136G>A (p.Gly46Ser)
HGVS:
  • NC_000012.12:g.102912823C>T
  • NG_008690.2:g.50588G>A
  • NM_000277.3:c.136G>AMANE SELECT
  • NM_001354304.2:c.136G>A
  • NP_000268.1:p.Gly46Ser
  • NP_001341233.1:p.Gly46Ser
  • NC_000012.11:g.103306601C>T
  • NM_000277.1:c.136G>A
  • NM_000277.3(PAH):c.136G>AMANE SELECT
  • P00439:p.Gly46Ser
Protein change:
G46S; GLY46SER
Links:
UniProtKB: P00439#VAR_000875; OMIM: 612349.0055; dbSNP: rs74603784
NCBI 1000 Genomes Browser:
rs74603784
Molecular consequence:
  • NM_000277.3:c.136G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.136G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003735011Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Feb 7, 2022) 		germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

In vivo assessment of mutations in the phenylalanine hydroxylase gene by phenylalanine loading: characterization of seven common mutations.

Guldberg P, Mikkelsen I, Henriksen KF, Lou HC, Güttler F.

Eur J Pediatr. 1995 Jul;154(7):551-6.

PubMed [citation]
PMID:
7556322

Molecular analysis of phenylketonuria in Denmark: 99% of the mutations detected by denaturing gradient gel electrophoresis.

Guldberg P, Henriksen KF, Güttler F.

Genomics. 1993 Jul;17(1):141-6.

PubMed [citation]
PMID:
8406445
See all PubMed Citations (14)

Details of each submission

From Ambry Genetics, SCV003735011.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (14)

Description

The c.136G>A (p.G46S) alteration is located in exon 2 (coding exon 2) of the PAH gene. This alteration results from a G to A substitution at nucleotide position 136, causing the glycine (G) at amino acid position 46 to be replaced by a serine (S). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (21/282814) total alleles studied. The highest observed frequency was 0.02% (20/129138) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state, and in the compound heterozygous state in conjunction with another pathogenic PAH mutation, in multiple unrelated individuals with phenylalanine hydroxylase (PAH) deficiency (Ferreira, 2021; Aldamiz-Echevarria, 2016; Bueno, 2013; Trunzo, 2015; Couce, 2013; Guldberg, 1993; Guldberg, 1998; Eiken, 1996). In vitro experimental studies show that the G46S alteration impacts protein function (Leandro, 2011; Eiken, 1996; Shi, 2012; Gjetting, 2001; Couce, 2013, Leandro, 2017). Based on the available evidence, this alteration is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024