NM_000277.3(PAH):c.30C>G (p.Gly10=) AND Phenylketonuria

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Aug 14, 2023
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:: RCV000779088.15

Allele description [Variation Report for NM_000277.3(PAH):c.30C>G (p.Gly10=)]

NM_000277.3(PAH):c.30C>G (p.Gly10=)

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.30C>G (p.Gly10=)

HGVS:

NC_000012.12:g.102917101G>C
NG_008690.2:g.46310C>G
NM_000277.3:c.30C>GMANE SELECT
NM_001354304.2:c.30C>G
NP_000268.1:p.Gly10=
NP_001341233.1:p.Gly10=
NC_000012.11:g.103310879G>C
NM_000277.1:c.30C>G

Links:

dbSNP: rs1801145

NCBI 1000 Genomes Browser:

rs1801145

Molecular consequence:

NM_000277.3:c.30C>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354304.2:c.30C>G - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV000915573	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Aug 23, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001418959	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 2018035, 20457534, 28492532
SCV002088681	Natera, Inc.	no assertion criteria provided	Uncertain significance (Dec 27, 2019)	germline	clinical testing
SCV002598523	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 18, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003816610	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 24, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004209619	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 14, 2023)	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	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

Different clinical manifestations of hyperphenylalaninemia in three siblings with identical phenylalanine hydroxylase genes.

DiSilvestre D, Koch R, Groffen J.

Am J Hum Genet. 1991 May;48(5):1014-6. No abstract available.

PubMed [citation]

PMID:: 2018035
PMCID:: PMC1683043

The phenylalanine hydroxylase c.30C>G synonymous variation (p.G10G) creates a common exonic splicing silencer.

Dobrowolski SF, Andersen HS, Doktor TK, Andresen BS.

Mol Genet Metab. 2010 Aug;100(4):316-23. doi: 10.1016/j.ymgme.2010.04.002. Epub 2010 Apr 14.

PubMed [citation]

PMID:: 20457534

See all PubMed Citations (4)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000915573.1

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

Description

The PAH gene is the only gene in which variants are known to cause phenylalanine hydroxylase deficiency. The PAH c.30C>G (p.Gly10=) synonymous variant has been reported in one study and found in a compound heterozygous state with an indel variant in one family with two affected siblings. The authors suggest that the c.30C>G variant may cause aberrant mRNA splicing. They observed an increase in binding of c.30C>G PAH RNA to heterogeneous nuclear ribonucleoprotein (hnRNP) proteins which inhibit splicing (Dobrowlski et al. 2010). The p.Gly10 variant was absent from 200 control individuals and is reported at a frequency of 0.00330 in the Other population of the Exome Aggregation Consortium. Based on the evidence, the p.Gly10 variant is classified as a variant of unknown significance but suspicious for pathogenicity for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001418959.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change affects codon 10 of the PAH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PAH protein. This variant is present in population databases (rs1801145, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with phenylketonuria (PKU) (PMID: 2018035, 20457534). ClinVar contains an entry for this variant (Variation ID: 102649). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 20457534). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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., SCV002088681.1

#	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 Centogene AG - the Rare Disease Company, SCV002598523.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003816610.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004209619.1

#	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: Oct 20, 2024

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