Variant summary: PAH c.1042C>G (p.Leu348Val) results in a conservative amino acid change located in the in the catalytic domain (Sarkissian 2011) 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 0.00011 in 276972 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00011 vs 0.0079), allowing no conclusion about variant significance. c.1042C>G has been reported in the literature in multiple individuals affected with the classic and mild form of Phenylalanine Hydroxylase Deficiency (i.e. Phenylketonuria) (e.g. Quirk 2012, Sarkissian 2011, Jeannesson-Thivisol 2015). 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 most pronounced variant effect results in 20%-40% of normal activity (see e.g. Benit 1999, Zurfluh 2008), with variable Bh4 responsivity, depending on the genotype (Sarkissian 2011, Jeannesson-Thivisol 2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.1042C>G (p.Leu348Val)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(19)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
19
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000277.3(PAH):c.1042C>G (p.Leu348Val)
Variation ID: 92727 Accession: VCV000092727.56
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q23.2 12: 102844359 (GRCh38) [ NCBI UCSC ] 12: 103238137 (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 Nov 24, 2024 Mar 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000277.3:c.1042C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Leu348Val missense NM_001354304.2:c.1042C>G NP_001341233.1:p.Leu348Val missense NC_000012.12:g.102844359G>C NC_000012.11:g.103238137G>C NG_008690.2:g.119052C>G P00439:p.Leu348Val - Protein change
- L348V
- Other names
- -
- Canonical SPDI
- NC_000012.12:102844358:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
Exome Aggregation Consortium (ExAC) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00011
The Genome Aggregation Database (gnomAD) 0.00014
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
1508 | 1631 | |
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. |
|---|---|---|---|---|
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2024 | RCV000078498.41 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2024 | RCV000150080.35 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Jan 7, 2022 | RCV002251963.9 |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 26, 2022 | RCV002514381.9 | |
|
PAH-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Nov 16, 2023 | RCV003944994.3 |
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
(Jul 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917927.1
First in ClinVar: May 31, 2019 Last updated: May 31, 2019 |
Comment:
Variant summary: PAH c.1042C>G (p.Leu348Val) results in a conservative amino acid change located in the in the catalytic domain (Sarkissian 2011) of the encoded protein … (more)
Variant summary: PAH c.1042C>G (p.Leu348Val) results in a conservative amino acid change located in the in the catalytic domain (Sarkissian 2011) 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 0.00011 in 276972 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00011 vs 0.0079), allowing no conclusion about variant significance. c.1042C>G has been reported in the literature in multiple individuals affected with the classic and mild form of Phenylalanine Hydroxylase Deficiency (i.e. Phenylketonuria) (e.g. Quirk 2012, Sarkissian 2011, Jeannesson-Thivisol 2015). 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 most pronounced variant effect results in 20%-40% of normal activity (see e.g. Benit 1999, Zurfluh 2008), with variable Bh4 responsivity, depending on the genotype (Sarkissian 2011, Jeannesson-Thivisol 2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002568327.1
First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022 |
Comment:
PS3_Moderate, PM2, PM3_Very Strong, PP3
|
|
|
Pathogenic
(Feb 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490682.3
First in ClinVar: Feb 02, 2015 Last updated: Mar 04, 2023 |
Comment:
Functional studies report the in vitro phenylalanine hydroxylase activity associated with L348V as 25-44% of wild type (Couce et al., 2013; Zurfluh et al., 2008; … (more)
Functional studies report the in vitro phenylalanine hydroxylase activity associated with L348V as 25-44% of wild type (Couce et al., 2013; Zurfluh et al., 2008; Pey et al., 2007), and that the mutant enzyme showed a substantial reduction in binding affinity for BH4, but stabilization by BH4 was similar to wild type (Dobrowolski et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Responsiveness to BH4 therapy is not clear (Zurflh et al., 2008; Dobrowolski et al., 2009; Aldmiz-Echevarra et al., 2016).; This variant is associated with the following publications: (PMID: 25750018, 10479481, 25087612, 18937047, 25596310, 21953985, 17924342, 17935162, 23500595, 28850634, 29102225, 30037505, 30648773, 31355225, 1301187, 27121329, 31589614, 32668217) (less)
|
|
|
Pathogenic
(Sep 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016506.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Sep 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003559979.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1042C>G (p.L348V) alteration is located in exon 10 (coding exon 10) of the PAH gene. This alteration results from a C to G substitution … (more)
The c.1042C>G (p.L348V) alteration is located in exon 10 (coding exon 10) of the PAH gene. This alteration results from a C to G substitution at nucleotide position 1042, causing the leucine (L) at amino acid position 348 to be replaced by a valine (V). Based on data from gnomAD, the G allele has an overall frequency of 0.011% (31/282614) total alleles studied. The highest observed frequency was 0.022% (28/129064) of European (non-Finnish) alleles. This variant has been detected in the homozygous state or in conjunction with a second PAH variant in multiple individuals with phenylalanine hydroxylase (PAH) deficiency (Bik_multanowski, 2013; Rajabi, 2019; Su, 2019; Jeannesson, 2015; Quirk, 2012). This amino acid position is highly conserved in available vertebrate species. Functional studies indicate this alteration impairs phenylalanine hydroxylase activity (Dobrowolski, 2009; Danecka, 2015; Himmelreich, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201327.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(May 20, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110354.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 23
Sex: mixed
|
|
|
Pathogenic
(Jan 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002522979.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PM2, PM3, PP3, PP4
Clinical Features:
Short stature (present) , Neurodevelopmental abnormality (present) , Hypertelorism (present) , Facial hemangioma (present)
|
|
|
Pathogenic
(Mar 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893268.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jul 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601705.3
First in ClinVar: Feb 02, 2015 Last updated: Jan 06, 2024 |
Comment:
The PAH c.1042C>G (p.Leu348Val) variant has been reported in the published literature in multiple individuals affected with classical phenylketonuria or mild hyperphenylalaninemia (PMIDs: 8632937 (1996), … (more)
The PAH c.1042C>G (p.Leu348Val) variant has been reported in the published literature in multiple individuals affected with classical phenylketonuria or mild hyperphenylalaninemia (PMIDs: 8632937 (1996), 9012412 (1997), 18937047 (2009), 26666653 (2015), 31355225 (2019), 33375644 (2020), 34828281 (2021)). Functional studies show that this variant is destabilizing, though improvement was observed with tetrahydrobiopterin (BH4) treatment (PMID: 30648773 (2019)). The variant was also reported to have lower BH4 binding affinity (PMID: 18937047 (2009)). In addition, the variant had a PAH activity range of 8-41% of the wild-type in vitro (PMIDs: 10479481 (1999), 17935162 (2008), 25596310 (2015), 30037505 (2018)). The frequency of this variant in the general population, 0.00043 (22/50764 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000629168.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 348 of the PAH protein (p.Leu348Val). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 348 of the PAH protein (p.Leu348Val). This variant is present in population databases (rs62516092, gnomAD 0.02%). This missense change has been observed in individuals with classic and mild phenylketonuria (PKU) (PMID: 1301187, 8632937, 18937047, 20082265). ClinVar contains an entry for this variant (Variation ID: 92727). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 10479481, 17935162, 23500595, 25596310). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249173.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
PAH: PM3:Very Strong, PS3, PM2, PP4:Moderate, PP3
Number of individuals with the variant: 4
|
|
|
Pathogenic
(Sep 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005414107.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP3, PP4, PM3_very_strong, PS3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 22, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000485384.2
First in ClinVar: Jun 28, 2015 Last updated: Aug 13, 2019 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927990.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958196.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463124.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Nov 16, 2023)
|
no assertion criteria provided
Method: clinical testing
|
PAH-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004758213.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The PAH c.1042C>G variant is predicted to result in the amino acid substitution p.Leu348Val. This variant has been reported in the homozygous state or heterozygous … (more)
The PAH c.1042C>G variant is predicted to result in the amino acid substitution p.Leu348Val. This variant has been reported in the homozygous state or heterozygous state with a second PAH variant in individuals with hyperphenylalaninemia (e.g., Eisensmith et al. 1992. PubMed ID: 1301187; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Himmelreich et al. 2018. PubMed ID: 30037505, Table S3 in Hillert et al. 2020. PubMed ID: 32668217). It has been associated with mild or classic phenylketonuria (PKU) (Réblová et al. 2015. PubMed ID: 25750018; Himmelreich et al. 2018. PubMed ID: 30037505). The p.Leu348 amino acid is located in the enzyme active site crevice (Dobrowolski et al. 2009. PubMed ID: 18937047) and the p.Leu348Val substitution has been reported to moderately reduce enzyme activity (Couce et al. 2013. PubMed ID: 23500595; Himmelreich et al. 2018. PubMed ID: 30037505). The p.Leu348Val amino acid substitution has been reported to lead to a PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). This variant has been interpreted as pathogenic by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/92727/). Taken together, we interpret this variant as pathogenic. (less)
|
|
|
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: SCV000119300.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
|
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Comment:
Comment:
PS3_Moderate, PM2, PM3_Very Strong, PP3
Comment:
Functional studies report the in vitro phenylalanine hydroxylase activity associated with L348V as 25-44% of wild type (Couce et al., 2013; Zurfluh et al., 2008; Pey et al., 2007), and that the mutant enzyme showed a substantial reduction in binding affinity for BH4, but stabilization by BH4 was similar to wild type (Dobrowolski et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Responsiveness to BH4 therapy is not clear (Zurflh et al., 2008; Dobrowolski et al., 2009; Aldmiz-Echevarra et al., 2016).; This variant is associated with the following publications: (PMID: 25750018, 10479481, 25087612, 18937047, 25596310, 21953985, 17924342, 17935162, 23500595, 28850634, 29102225, 30037505, 30648773, 31355225, 1301187, 27121329, 31589614, 32668217)
Comment:
The c.1042C>G (p.L348V) alteration is located in exon 10 (coding exon 10) of the PAH gene. This alteration results from a C to G substitution at nucleotide position 1042, causing the leucine (L) at amino acid position 348 to be replaced by a valine (V). Based on data from gnomAD, the G allele has an overall frequency of 0.011% (31/282614) total alleles studied. The highest observed frequency was 0.022% (28/129064) of European (non-Finnish) alleles. This variant has been detected in the homozygous state or in conjunction with a second PAH variant in multiple individuals with phenylalanine hydroxylase (PAH) deficiency (Bik_multanowski, 2013; Rajabi, 2019; Su, 2019; Jeannesson, 2015; Quirk, 2012). This amino acid position is highly conserved in available vertebrate species. Functional studies indicate this alteration impairs phenylalanine hydroxylase activity (Dobrowolski, 2009; Danecka, 2015; Himmelreich, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
ACMG classification criteria: PM2, PM3, PP3, PP4
Comment:
The PAH c.1042C>G (p.Leu348Val) variant has been reported in the published literature in multiple individuals affected with classical phenylketonuria or mild hyperphenylalaninemia (PMIDs: 8632937 (1996), 9012412 (1997), 18937047 (2009), 26666653 (2015), 31355225 (2019), 33375644 (2020), 34828281 (2021)). Functional studies show that this variant is destabilizing, though improvement was observed with tetrahydrobiopterin (BH4) treatment (PMID: 30648773 (2019)). The variant was also reported to have lower BH4 binding affinity (PMID: 18937047 (2009)). In addition, the variant had a PAH activity range of 8-41% of the wild-type in vitro (PMIDs: 10479481 (1999), 17935162 (2008), 25596310 (2015), 30037505 (2018)). The frequency of this variant in the general population, 0.00043 (22/50764 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 348 of the PAH protein (p.Leu348Val). This variant is present in population databases (rs62516092, gnomAD 0.02%). This missense change has been observed in individuals with classic and mild phenylketonuria (PKU) (PMID: 1301187, 8632937, 18937047, 20082265). ClinVar contains an entry for this variant (Variation ID: 92727). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 10479481, 17935162, 23500595, 25596310). For these reasons, this variant has been classified as Pathogenic.
Comment:
PAH: PM3:Very Strong, PS3, PM2, PP4:Moderate, PP3
Comment:
PP3, PP4, PM3_very_strong, PS3
Comment:
The PAH c.1042C>G variant is predicted to result in the amino acid substitution p.Leu348Val. This variant has been reported in the homozygous state or heterozygous state with a second PAH variant in individuals with hyperphenylalaninemia (e.g., Eisensmith et al. 1992. PubMed ID: 1301187; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Himmelreich et al. 2018. PubMed ID: 30037505, Table S3 in Hillert et al. 2020. PubMed ID: 32668217). It has been associated with mild or classic phenylketonuria (PKU) (Réblová et al. 2015. PubMed ID: 25750018; Himmelreich et al. 2018. PubMed ID: 30037505). The p.Leu348 amino acid is located in the enzyme active site crevice (Dobrowolski et al. 2009. PubMed ID: 18937047) and the p.Leu348Val substitution has been reported to moderately reduce enzyme activity (Couce et al. 2013. PubMed ID: 23500595; Himmelreich et al. 2018. PubMed ID: 30037505). The p.Leu348Val amino acid substitution has been reported to lead to a PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). This variant has been interpreted as pathogenic by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/92727/). Taken together, we interpret this variant 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:
Variant summary: PAH c.1042C>G (p.Leu348Val) results in a conservative amino acid change located in the in the catalytic domain (Sarkissian 2011) 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 0.00011 in 276972 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00011 vs 0.0079), allowing no conclusion about variant significance. c.1042C>G has been reported in the literature in multiple individuals affected with the classic and mild form of Phenylalanine Hydroxylase Deficiency (i.e. Phenylketonuria) (e.g. Quirk 2012, Sarkissian 2011, Jeannesson-Thivisol 2015). 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 most pronounced variant effect results in 20%-40% of normal activity (see e.g. Benit 1999, Zurfluh 2008), with variable Bh4 responsivity, depending on the genotype (Sarkissian 2011, Jeannesson-Thivisol 2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PS3_Moderate, PM2, PM3_Very Strong, PP3
Comment:
Functional studies report the in vitro phenylalanine hydroxylase activity associated with L348V as 25-44% of wild type (Couce et al., 2013; Zurfluh et al., 2008; Pey et al., 2007), and that the mutant enzyme showed a substantial reduction in binding affinity for BH4, but stabilization by BH4 was similar to wild type (Dobrowolski et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Responsiveness to BH4 therapy is not clear (Zurflh et al., 2008; Dobrowolski et al., 2009; Aldmiz-Echevarra et al., 2016).; This variant is associated with the following publications: (PMID: 25750018, 10479481, 25087612, 18937047, 25596310, 21953985, 17924342, 17935162, 23500595, 28850634, 29102225, 30037505, 30648773, 31355225, 1301187, 27121329, 31589614, 32668217)
Comment:
The c.1042C>G (p.L348V) alteration is located in exon 10 (coding exon 10) of the PAH gene. This alteration results from a C to G substitution at nucleotide position 1042, causing the leucine (L) at amino acid position 348 to be replaced by a valine (V). Based on data from gnomAD, the G allele has an overall frequency of 0.011% (31/282614) total alleles studied. The highest observed frequency was 0.022% (28/129064) of European (non-Finnish) alleles. This variant has been detected in the homozygous state or in conjunction with a second PAH variant in multiple individuals with phenylalanine hydroxylase (PAH) deficiency (Bik_multanowski, 2013; Rajabi, 2019; Su, 2019; Jeannesson, 2015; Quirk, 2012). This amino acid position is highly conserved in available vertebrate species. Functional studies indicate this alteration impairs phenylalanine hydroxylase activity (Dobrowolski, 2009; Danecka, 2015; Himmelreich, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
ACMG classification criteria: PM2, PM3, PP3, PP4
Comment:
The PAH c.1042C>G (p.Leu348Val) variant has been reported in the published literature in multiple individuals affected with classical phenylketonuria or mild hyperphenylalaninemia (PMIDs: 8632937 (1996), 9012412 (1997), 18937047 (2009), 26666653 (2015), 31355225 (2019), 33375644 (2020), 34828281 (2021)). Functional studies show that this variant is destabilizing, though improvement was observed with tetrahydrobiopterin (BH4) treatment (PMID: 30648773 (2019)). The variant was also reported to have lower BH4 binding affinity (PMID: 18937047 (2009)). In addition, the variant had a PAH activity range of 8-41% of the wild-type in vitro (PMIDs: 10479481 (1999), 17935162 (2008), 25596310 (2015), 30037505 (2018)). The frequency of this variant in the general population, 0.00043 (22/50764 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 348 of the PAH protein (p.Leu348Val). This variant is present in population databases (rs62516092, gnomAD 0.02%). This missense change has been observed in individuals with classic and mild phenylketonuria (PKU) (PMID: 1301187, 8632937, 18937047, 20082265). ClinVar contains an entry for this variant (Variation ID: 92727). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 10479481, 17935162, 23500595, 25596310). For these reasons, this variant has been classified as Pathogenic.
Comment:
PAH: PM3:Very Strong, PS3, PM2, PP4:Moderate, PP3
Comment:
PP3, PP4, PM3_very_strong, PS3
Comment:
The PAH c.1042C>G variant is predicted to result in the amino acid substitution p.Leu348Val. This variant has been reported in the homozygous state or heterozygous state with a second PAH variant in individuals with hyperphenylalaninemia (e.g., Eisensmith et al. 1992. PubMed ID: 1301187; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Himmelreich et al. 2018. PubMed ID: 30037505, Table S3 in Hillert et al. 2020. PubMed ID: 32668217). It has been associated with mild or classic phenylketonuria (PKU) (Réblová et al. 2015. PubMed ID: 25750018; Himmelreich et al. 2018. PubMed ID: 30037505). The p.Leu348 amino acid is located in the enzyme active site crevice (Dobrowolski et al. 2009. PubMed ID: 18937047) and the p.Leu348Val substitution has been reported to moderately reduce enzyme activity (Couce et al. 2013. PubMed ID: 23500595; Himmelreich et al. 2018. PubMed ID: 30037505). The p.Leu348Val amino acid substitution has been reported to lead to a PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). This variant has been interpreted as pathogenic by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/92727/). Taken together, we interpret this variant as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations. | Vela-Amieva M | Genes | 2021 | PMID: 34828281 |
| Phenylketonuria in Portugal: Genotype-phenotype correlations using molecular, biochemical, and haplotypic analyses. | Ferreira F | Molecular genetics & genomic medicine | 2021 | PMID: 33465300 |
| Phenylketonuria Diagnosis by Massive Parallel Sequencing and Genotype-Phenotype Association in Brazilian Patients. | Tresbach RH | Genes | 2020 | PMID: 33375644 |
| Phenylalanine hydroxylase genotype-phenotype associations in the United States: A single center study. | Rajabi F | Molecular genetics and metabolism | 2019 | PMID: 31623983 |
| The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra. | Su Y | Annals of translational medicine | 2019 | PMID: 31355225 |
| Toward mechanistic models for genotype-phenotype correlations in phenylketonuria using protein stability calculations. | Scheller R | Human mutation | 2019 | PMID: 30648773 |
| Relationship between genotype, phenylalanine hydroxylase expression and in vitro activity and metabolic phenotype in phenylketonuria. | Himmelreich N | Molecular genetics and metabolism | 2018 | PMID: 30037505 |
| "Mild" hyperphenylalaninemia? A case series of seven treated patients following newborn screening. | Viall S | Molecular genetics and metabolism | 2017 | PMID: 29102225 |
| Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness. | Jeannesson-Thivisol E | Orphanet journal of rare diseases | 2015 | PMID: 26666653 |
| Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria. | Danecka MK | Journal of medical genetics | 2015 | PMID: 25596310 |
| Influence of PAH Genotype on Sapropterin Response in PKU: Results of a Single-Center Cohort Study. | Leuders S | JIMD reports | 2014 | PMID: 24190797 |
| Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness. | Bik-Multanowski M | Acta biochimica Polonica | 2013 | PMID: 24350308 |
| Molecular epidemiology and BH4-responsiveness in patients with phenylalanine hydroxylase deficiency from Galicia region of Spain. | Couce ML | Gene | 2013 | PMID: 23500595 |
| Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response? | Sarkissian CN | JIMD reports | 2012 | PMID: 23430918 |
| Utility of phenylalanine hydroxylase genotype for tetrahydrobiopterin responsiveness classification in patients with phenylketonuria. | Quirk ME | Molecular genetics and metabolism | 2012 | PMID: 22841515 |
| Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase. | Shi Z | Proteins | 2012 | PMID: 21953985 |
| Variations in genotype-phenotype correlations in phenylketonuria patients. | Santos LL | Genetics and molecular research : GMR | 2010 | PMID: 20082265 |
| Biochemical characterization of mutant phenylalanine hydroxylase enzymes and correlation with clinical presentation in hyperphenylalaninaemic patients. | Dobrowolski SF | Journal of inherited metabolic disease | 2009 | PMID: 18937047 |
| Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. | Zurflüh MR | Human mutation | 2008 | PMID: 17935162 |
| Tetrahydrobiopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype. | Desviat LR | Molecular genetics and metabolism | 2004 | PMID: 15464430 |
| Mutational spectrum in German patients with phenylalanine hydroxylase deficiency. | Aulehla-Scholz C | Human mutation | 2003 | PMID: 12655553 |
| Molecular basis of phenylketonuria in Cuba. | Desviat LR | Human mutation | 2001 | PMID: 11524738 |
| Molecular analysis of phenylketonuria (PKU) in newborns from Texas. | Yang Y | Human mutation | 2001 | PMID: 11385716 |
| Mutations of the phenylalanine hydroxylase (PAH) gene in Brazilian patients with phenylketonuria. | Acosta A | Human mutation | 2001 | PMID: 11180595 |
| Phenylketonuria and hyperphenylalaninemia in eastern Germany: a characteristic molecular profile and 15 novel mutations. | Hennermann JB | Human mutation | 2000 | PMID: 10679941 |
| The mutant genotype is the main determinant of the metabolic phenotype in phenylalanine hydroxylase deficiency. | Bénit P | Molecular genetics and metabolism | 1999 | PMID: 10479481 |
| Sequence variation at the phenylalanine hydroxylase gene in the British Isles. | Tyfield LA | American journal of human genetics | 1997 | PMID: 9012412 |
| Molecular basis of phenylketonuria and a correlation between genotype and phenotype in a heterogeneous southeastern US population. | Eisensmith RC | Pediatrics | 1996 | PMID: 8632937 |
| Phenylketonuria mutation analysis in Northern Ireland: a rapid stepwise approach. | Zschocke J | American journal of human genetics | 1995 | PMID: 8533759 |
| Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene. | Eisensmith RC | Human mutation | 1992 | PMID: 1301187 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
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Text-mined citations for rs62516092 ...
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.