VCV000000629.95 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

9 submissions

9 submitters

3 conditions

Reviewed by expert panel

Pathogenic

Dec 2019 by ClinGen PAH Va… FDA Recognized Database

for Phenylketonuria

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 629 Accession: VCV000000629.95

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q23.2 12: 102912823 (GRCh38) [ NCBI UCSC ] 12: 103306601 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 19, 2014	Jun 17, 2024	Dec 22, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NM_000277.3(PAH):c.136G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000277.3:c.136G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000268.1:p.Gly46Ser	missense
NM_001354304.2:c.136G>A	NP_001341233.1:p.Gly46Ser	missense
NC_000012.12:g.102912823C>T
NC_000012.11:g.103306601C>T
NG_008690.2:g.50588G>A
	P00439:p.Gly46Ser

... more HGVS ... less HGVS

Protein change

G46S

Other names

Canonical SPDI

NC_000012.12:102912822:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00008

Exome Aggregation Consortium (ExAC) 0.00012

Links

ClinGen: CA229439 UniProtKB: P00439#VAR_000875 OMIM: 612349.0055 dbSNP: rs74603784 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PAH		-	-	GRCh38 GRCh37	1506	1629

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Phenylketonuria	Pathogenic (7)	reviewed by expert panel	Dec 22, 2019	RCV000000661.91
not provided	not provided (1)	no classification provided	-	RCV000088836.7
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Feb 7, 2022	RCV002512613.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 22, 2019)	reviewed by expert panel (ClinGen PAH ACMG Specifications v1) Method: curation	Phenylketonuria (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen PAH Variant Curation Expert Panel FDA Recognized Database Accession: SCV001250543.1 First in ClinVar: May 12, 2020 Last updated: May 12, 2020	Publications: PubMed (4) PubMed: 8829656‚ 7556322‚ 11161839‚ 23514811 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6640c833-7378-4d20-bf7f-32178b1c5c6a Comment: The PAH variant c.136G>A (p.Gly46Ser) was detected in four alleles associated with moderate PKU (phenylalanine values of 900-1200 micromol/L). Patients included in the study had … (more) The PAH variant c.136G>A (p.Gly46Ser) was detected in four alleles associated with moderate PKU (phenylalanine values of 900-1200 micromol/L). Patients included in the study had serum phenylalanine levels above 150 micromol/L and normal urinary excretion of biopterin and neopterin (PMID: 7556322). The variant c.136G>A (p.Gly46Ser) was documented in trans with seven other PAH pathogenic or likely pathogenic variants in 15 Norwegian patients with mild and classic PKU. Haplotype analysis of index cases and parents was conducted, when necessary siblings were also investigated (PMID: 8829656). PM3_Very Strong (14 points). In vitro, enzyme activity assays demonstrated a residual activity for the PAH variant c.136G>A (p.Gly46Ser) between 26% and 38% compared to the wild type PAH when using the mammalian cell-free transcription-translation system (PMID: 11161839). According to gnomAD, this variant is present at a low allele frequency in population databases, with the highest reported frequency in the European (Non-Finnish) population (0.00015). In silico modeling, predictions are conflicting. According to SIFT this variant is predicted to be tolerated, probably damaging by Polyphen 2-HVAR and disease-causing Automatic by Mutation Taster. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Very Strong, PP4 met_moderate, and PS3. (less)
Pathogenic (Nov 19, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917930.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (2) PubMed: 23514811‚ 8831077 Comment: Variant summary: PAH c.136G>A (p.Gly46Ser) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of … (more) Variant summary: PAH c.136G>A (p.Gly46Ser) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 277146 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (7.6e-05 vs 0.0079), allowing no conclusion about variant significance. c.136G>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (e.g. Bueno_2013, Eiken_1996). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The variant effect resulted in a smaller than 30% of normal activity (Bueno_2013, Eiken_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002813885.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Dec 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000835867.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 28492532‚ 7556322‚ 9634518‚ 23500595‚ 26210745‚ 8829656‚ 11326337‚ 20937381‚ 21953985‚ 28174686 Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 46 of the PAH protein (p.Gly46Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 46 of the PAH protein (p.Gly46Ser). This variant is present in population databases (rs74603784, gnomAD 0.02%). This missense change has been observed in individuals with PAH-related conditions (PMID: 7556322, 9634518, 23500595, 26210745). ClinVar contains an entry for this variant (Variation ID: 629). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 8829656, 11326337, 20937381, 21953985, 23500595, 28174686). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 07, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003735011.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (14) PubMed: 7556322‚ 8406445‚ 8829656‚ 9634518‚ 11161839‚ 11326337‚ 20937381‚ 21953985‚ 23500595‚ 23514811‚ 26210745‚ 27121329‚ 28174686‚ 33465300 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004201379.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jan 01, 1996)	no assertion criteria provided Method: literature only	PHENYLKETONURIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020811.67 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 8829656 Comment on evidence: Eiken et al. (1996) demonstrated a gly46-to-ser (G46S) mutation in the PAH gene in phenylketonuria (PKU; 261600) patients and studied its phenotypic consequences in 3 … (more) Eiken et al. (1996) demonstrated a gly46-to-ser (G46S) mutation in the PAH gene in phenylketonuria (PKU; 261600) patients and studied its phenotypic consequences in 3 homozygotes and 13 compound heterozygotes. DNA sequencing following fluorescence-based SSCP revealed a G-to-A transition at their cDNA position 136. The G46S mutation was present in 17 of 236 Norwegian PKU alleles (7.2%) and in 8 of 176 Swedish PKU alleles (4.5%). Three patients were homozygous for the G46S mutation; 2 were untreated and had mild and severe mental retardation, respectively. Studies with an in vitro transcription-transition system revealed an abnormal susceptibility of the mutant enzyme to form catalytically inactive high-molecular-mass aggregates. This aggregation of the mutant protein, followed by increased cellular degradation, was compatible with the clinical/metabolic phenotype of the affected patients. (less)
Pathogenic (Oct 16, 2020)	no assertion criteria provided Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002088677.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE Accession: SCV000119428.1 First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014

Comment:

The PAH variant c.136G>A (p.Gly46Ser) was detected in four alleles associated with moderate PKU (phenylalanine values of 900-1200 micromol/L). Patients included in the study had serum phenylalanine levels above 150 micromol/L and normal urinary excretion of biopterin and neopterin (PMID: 7556322). The variant c.136G>A (p.Gly46Ser) was documented in trans with seven other PAH pathogenic or likely pathogenic variants in 15 Norwegian patients with mild and classic PKU. Haplotype analysis of index cases and parents was conducted, when necessary siblings were also investigated (PMID: 8829656). PM3_Very Strong (14 points). In vitro, enzyme activity assays demonstrated a residual activity for the PAH variant c.136G>A (p.Gly46Ser) between 26% and 38% compared to the wild type PAH when using the mammalian cell-free transcription-translation system (PMID: 11161839). According to gnomAD, this variant is present at a low allele frequency in population databases, with the highest reported frequency in the European (Non-Finnish) population (0.00015). In silico modeling, predictions are conflicting. According to SIFT this variant is predicted to be tolerated, probably damaging by Polyphen 2-HVAR and disease-causing Automatic by Mutation Taster. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Very Strong, PP4 met_moderate, and PS3.

Comment:

Variant summary: PAH c.136G>A (p.Gly46Ser) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 277146 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (7.6e-05 vs 0.0079), allowing no conclusion about variant significance. c.136G>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (e.g. Bueno_2013, Eiken_1996). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The variant effect resulted in a smaller than 30% of normal activity (Bueno_2013, Eiken_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 46 of the PAH protein (p.Gly46Ser). This variant is present in population databases (rs74603784, gnomAD 0.02%). This missense change has been observed in individuals with PAH-related conditions (PMID: 7556322, 9634518, 23500595, 26210745). ClinVar contains an entry for this variant (Variation ID: 629). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 8829656, 11326337, 20937381, 21953985, 23500595, 28174686). For these reasons, this variant has been classified as Pathogenic.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Phenylketonuria in Portugal: Genotype-phenotype correlations using molecular, biochemical, and haplotypic analyses.	Ferreira F	Molecular genetics & genomic medicine	2021	PMID: 33465300
PKU mutation p.G46S prevents the stereospecific binding of l-phenylalanine to the dimer of human phenylalanine hydroxylase regulatory domain.	Leandro J	FEBS open bio	2017	PMID: 28174686
Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.	Aldámiz-Echevarría L	Journal of human genetics	2016	PMID: 27121329
Phenylalanine hydroxylase deficiency in south Italy: Genotype-phenotype correlations, identification of a novel mutant PAH allele and prediction of BH4 responsiveness.	Trunzo R	Clinica chimica acta; international journal of clinical chemistry	2015	PMID: 26210745
Molecular epidemiology and genotype-phenotype correlation in phenylketonuria patients from South Spain.	Bueno MA	Journal of human genetics	2013	PMID: 23514811
Molecular epidemiology and BH4-responsiveness in patients with phenylalanine hydroxylase deficiency from Galicia region of Spain.	Couce ML	Gene	2013	PMID: 23500595
Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase.	Shi Z	Proteins	2012	PMID: 21953985
Phenylketonuria as a protein misfolding disease: The mutation pG46S in phenylalanine hydroxylase promotes self-association and fibril formation.	Leandro J	Biochimica et biophysica acta	2011	PMID: 20937381
Missense mutations in the N-terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine.	Gjetting T	American journal of human genetics	2001	PMID: 11326337
In vitro expression of 34 naturally occurring mutant variants of phenylalanine hydroxylase: correlation with metabolic phenotypes and susceptibility toward protein aggregation.	Gjetting T	Molecular genetics and metabolism	2001	PMID: 11161839
A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype.	Guldberg P	American journal of human genetics	1998	PMID: 9634518
Phenylketonuria genotypes correlated to metabolic phenotype groups in Norway.	Eiken HG	European journal of pediatrics	1996	PMID: 8831077
PKU mutation G46S is associated with increased aggregation and degradation of the phenylalanine hydroxylase enzyme.	Eiken HG	Human mutation	1996	PMID: 8829656
In vivo assessment of mutations in the phenylalanine hydroxylase gene by phenylalanine loading: characterization of seven common mutations.	Guldberg P	European journal of pediatrics	1995	PMID: 7556322
Molecular analysis of phenylketonuria in Denmark: 99% of the mutations detected by denaturing gradient gel electrophoresis.	Guldberg P	Genomics	1993	PMID: 8406445
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6640c833-7378-4d20-bf7f-32178b1c5c6a	-	-	-	-
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Text-mined citations for rs74603784 ...

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Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs74603784 ...