VCV000000596.113 - ClinVar

NM_000277.3(PAH):c.814G>T (p.Gly272Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

19 submissions

19 submitters

3 conditions

Reviewed by expert panel

Pathogenic

Aug 2018 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.814G>T (p.Gly272Ter)

Variation ID: 596 Accession: VCV000000596.113

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q23.2 12: 102852843 (GRCh38) [ NCBI UCSC ] 12: 103246621 (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	Aug 10, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_000277.3:c.814G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000268.1:p.Gly272Ter	nonsense
NM_001354304.2:c.814G>T	NP_001341233.1:p.Gly272Ter	nonsense
NC_000012.12:g.102852843C>A
NC_000012.11:g.103246621C>A
NG_008690.2:g.110568G>T

... more HGVS ... less HGVS

Protein change

G272*

Other names

p.G272*:GGA>TGA
NM_000277.1(PAH):c.814G>T
p.Gly272*

Canonical SPDI

NC_000012.12:102852842:C:A

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00004

The Genome Aggregation Database (gnomAD) 0.00006

Links

ClinGen: CA251532 OMIM: 612349.0020 dbSNP: rs62514952 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	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.
Phenylketonuria	Pathogenic (10)	reviewed by expert panel	Aug 10, 2018	RCV000000627.96
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Apr 7, 2024	RCV000089110.21
PAH-related disorder	Pathogenic (1)	no assertion criteria provided	Feb 13, 2024	RCV003914791.3

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 (Aug 10, 2018)	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: SCV000852120.4 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022	Publications: PubMed (1) PubMed: 1975559 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f7c77032-c599-46f3-9086-0bb73eb5c0c1 Comment: PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extrememly low frequency in ExAC, gnomAD (MAF= 0.00006, 0.0003093); PVS1: Nonsense variant. Predicted to cause loss … (more) PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extrememly low frequency in ExAC, gnomAD (MAF= 0.00006, 0.0003093); PVS1: Nonsense variant. Predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.; PP4: G272X found on one allele of a patient with classic PKU (PMID:1975559). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4). (less)
Pathogenic (Aug 31, 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: SCV000919920.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (1) PubMed: 26666653 Comment: Variant summary: PAH c.814G>T (p.Gly272X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: PAH c.814G>T (p.Gly272X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.1e-05 in 277088 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (5.1e-05 vs 0.0079), allowing no conclusion about variant significance. c.814G>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Jeannesson-Thivisol_2015, Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. The variant was found to cause a loss of enzyme activity via functional studies (Aldamiz-Echevarria_2016). Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Dec 09, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194050.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (6) PubMed: 1671881‚ 24350308‚ 1978553‚ 10471838‚ 1975559‚ 12655550 Comment: NM_000277.1(PAH):c.814G>T(G272) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and is associated with the classic form of disease. Sources cited for classification … (more) NM_000277.1(PAH):c.814G>T(G272) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and is associated with the classic form of disease. Sources cited for classification include the following: PMID 1671881, 24350308, 1978553, 10471838, 1975559 and 12655550. Classification of NM_000277.1(PAH):c.814G>T(G272*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (May 15, 2018)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000888354.2 First in ClinVar: Oct 09, 2016 Last updated: Jan 01, 2022
Pathogenic (Jan 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002016483.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Phenylketonuria Affected status: yes Allele origin: germline	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Study: NSIGHT-NC NEXUS Accession: SCV001251473.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (7) PubMed: 20301677‚ 8370573‚ 1975559‚ 1978553‚ 17935162‚ 10471838‚ 12655550 Comment: The PAH c.814G>T (p.G272) nonsense variant is predicted to result in premature termination of the PAH protein and/or nonsense-mediated decay. This variant has been previously … (more) The PAH c.814G>T (p.G272) nonsense variant is predicted to result in premature termination of the PAH protein and/or nonsense-mediated decay. This variant has been previously reported as pathogenic in individuals with phenylketonuria (PMID: 8370573; 1975559; 1978553; 17935162; 10471838; 12655550). (less) Number of individuals with the variant: 1
Pathogenic (Oct 05, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV001468124.1 First in ClinVar: Jan 09, 2021 Last updated: Jan 09, 2021	Comment on evidence: PVS1, PP4, PM2
Pathogenic (Sep 02, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000239074.10 First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023	Comment: Reported in multiple patients with classic PKU, and one patient with mild PKU, in the presence of a second variant; also reported in a patient … (more) Reported in multiple patients with classic PKU, and one patient with mild PKU, in the presence of a second variant; also reported in a patient with classic PKU in the homozygous state (Svensson et al., 1990; Jeannesson-Thivisol et al., 2015; Williams et al., 2015); Associated with approximately 6%-7% residual activity compared to wild-type (Ho et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Classified as not responsive to BH4 therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 8444221, 10471838, 17935162, 22975760, 25525159, 23532445, 1975559, 25551302, 8889583, 29555771, 29431110, 31980526, 32668217, 33101986, 8188310, 32853555, 31589614, 26666653, 33375644, 27535533) (less)
Pathogenic (Dec 25, 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: SCV000754076.8 First in ClinVar: Oct 23, 2016 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 28492532‚ 1301187‚ 9634518‚ 1975559‚ 10471838 Comment: This sequence change creates a premature translational stop signal (p.Gly272) in the PAH gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gly272) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62514952, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with PKU (PMID: 1975559, 10471838). ClinVar contains an entry for this variant (Variation ID: 596). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Phenylketonuria Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051911.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004209581.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Apr 07, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005414111.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (4) PubMed: 10471838‚ 17935162‚ 1975559‚ 32668217 Comment: PP4, PM2_moderate, PM3, PVS1 Number of individuals with the variant: 4
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453102.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973806.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Feb 13, 2024)	no assertion criteria provided Method: clinical testing	PAH-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004736008.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The PAH c.814G>T variant is predicted to result in premature protein termination (p.Gly272). This variant has been reported in the homozygous state or with a … (more) The PAH c.814G>T variant is predicted to result in premature protein termination (p.Gly272). This variant has been reported in the homozygous state or with a second pathogenic PAH variant in many patients with phenylalanine hydroxylase deficiency (for example, see Table S3 in Hillert A et al 2020. PubMed ID: 32668217). This variant and has been reported to essentially abolish PAH enzyme activity, and patients with this variant have been reported to be non-responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). (Zurflüh et al. 2008. PubMed ID: 17935162). In the homozygous state, the c.814G>T variant has been associated with classical phenylketonuria (PKU) (Ellingsen et al. 1999. PubMed ID: 10471838). The ClinGen PAH Curation Expert Panel and multiple other outside laboratories classify this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/596/). Nonsense variants in PAH are expected to be pathogenic. Based on these observations, we also interpret this variant as pathogenic. (less)
Pathogenic (Sep 01, 1993)	no assertion criteria provided Method: literature only	PHENYLKETONURIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020777.67 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 1975559‚ 1978553‚ 1671881‚ 8370573 Comment on evidence: In a patient with classic phenylketonuria (PKU; 261600), Svensson et al. (1990) identified compound heterozygosity for a G-to-T transversion in the PAH gene, resulting in … (more) In a patient with classic phenylketonuria (PKU; 261600), Svensson et al. (1990) identified compound heterozygosity for a G-to-T transversion in the PAH gene, resulting in a gly272-to-ter (G272X) substitution, and a deletion of CTT leucine codon 364 (612349.0021). In 47 Norwegian nuclear families with at least 1 child with PKU, Apold et al. (1990) found haplotype 7, which is relatively rare in other populations, in 20% of all mutant haplotypes. In 14 of the 17 mutant haplotypes 7, a deletion of the BamHI restriction site in exon 7 of the PAH gene was found. The abrogation of the site was shown to be due to a G-to-T transversion, changing glycine-272 to a stop codon in exon 7. The families with this mutation were clustered along the southeastern coast of Norway, suggesting a founder effect. Melle et al. (1991) found the same mutation on the background of RFLP haplotype 7 in patients from northeastern France or Belgium. Apold et al. (1993) compiled data on the frequency of the G272X mutation in European populations. The mutation occurs north of the Alps and has a particularly high frequency in the Oslo Fjord region of Norway with the adjacent Bohuslan region of Sweden. An intermediate frequency was noted in the eastern part of Germany with the adjacent western part of Czechoslovakia. Genealogic studies revealed no common source for this mutation, but there was some geographic convergence to the Bohuslan region. The findings suggested a single origin for this mutation, with at least one founding population in southeastern Norway/adjacent Sweden. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741618.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
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: SCV001927778.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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: SCV000119717.1 First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014
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Comment:

PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extrememly low frequency in ExAC, gnomAD (MAF= 0.00006, 0.0003093); PVS1: Nonsense variant. Predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.; PP4: G272X found on one allele of a patient with classic PKU (PMID:1975559). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4).

Comment:

Variant summary: PAH c.814G>T (p.Gly272X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.1e-05 in 277088 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (5.1e-05 vs 0.0079), allowing no conclusion about variant significance. c.814G>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Jeannesson-Thivisol_2015, Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. The variant was found to cause a loss of enzyme activity via functional studies (Aldamiz-Echevarria_2016). Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

NM_000277.1(PAH):c.814G>T(G272*) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and is associated with the classic form of disease. Sources cited for classification include the following: PMID 1671881, 24350308, 1978553, 10471838, 1975559 and 12655550. Classification of NM_000277.1(PAH):c.814G>T(G272*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Comment:

The PAH c.814G>T (p.G272*) nonsense variant is predicted to result in premature termination of the PAH protein and/or nonsense-mediated decay. This variant has been previously reported as pathogenic in individuals with phenylketonuria (PMID: 8370573; 1975559; 1978553; 17935162; 10471838; 12655550).

Comment:

Reported in multiple patients with classic PKU, and one patient with mild PKU, in the presence of a second variant; also reported in a patient with classic PKU in the homozygous state (Svensson et al., 1990; Jeannesson-Thivisol et al., 2015; Williams et al., 2015); Associated with approximately 6%-7% residual activity compared to wild-type (Ho et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Classified as not responsive to BH4 therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 8444221, 10471838, 17935162, 22975760, 25525159, 23532445, 1975559, 25551302, 8889583, 29555771, 29431110, 31980526, 32668217, 33101986, 8188310, 32853555, 31589614, 26666653, 33375644, 27535533)

Comment:

This sequence change creates a premature translational stop signal (p.Gly272*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62514952, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with PKU (PMID: 1975559, 10471838). ClinVar contains an entry for this variant (Variation ID: 596). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The PAH c.814G>T variant is predicted to result in premature protein termination (p.Gly272*). This variant has been reported in the homozygous state or with a second pathogenic PAH variant in many patients with phenylalanine hydroxylase deficiency (for example, see Table S3 in Hillert A et al 2020. PubMed ID: 32668217). This variant and has been reported to essentially abolish PAH enzyme activity, and patients with this variant have been reported to be non-responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). (Zurflüh et al. 2008. PubMed ID: 17935162). In the homozygous state, the c.814G>T variant has been associated with classical phenylketonuria (PKU) (Ellingsen et al. 1999. PubMed ID: 10471838). The ClinGen PAH Curation Expert Panel and multiple other outside laboratories classify this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/596/). Nonsense variants in PAH are expected to be pathogenic. Based on these observations, we also 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The Genetic Landscape and Epidemiology of Phenylketonuria.	Hillert A	American journal of human genetics	2020	PMID: 32668217
Phenylalanine Hydroxylase Deficiency.	Adam MP	-	2017	PMID: 20301677
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
Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness.	Bik-Multanowski M	Acta biochimica Polonica	2013	PMID: 24350308
Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.	Zurflüh MR	Human mutation	2008	PMID: 17935162
The molecular basis of phenylketonuria in Lithuania.	Kasnauskiene J	Human mutation	2003	PMID: 12655550
Diverse PAH transcripts in lymphocytes of PKU patients with putative nonsense (G272X, Y356X) and missense (P281L, R408Q) mutations.	Ellingsen S	FEBS letters	1999	PMID: 10471838
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
The phenylketonuria G272X haplotype 7 mutation in European populations.	Apold J	Human genetics	1993	PMID: 8370573
Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.	Eisensmith RC	Human mutation	1992	PMID: 1301187
Two distinct mutations at a single BamHI site in phenylketonuria.	Melle D	Journal of medical genetics	1991	PMID: 1671881
A termination mutant prevalent in Norwegian haplotype 7 phenylketonuria genes.	Apold J	American journal of human genetics	1990	PMID: 1978553
Two mutations within the coding sequence of the phenylalanine hydroxylase gene.	Svensson E	Human genetics	1990	PMID: 1975559
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f7c77032-c599-46f3-9086-0bb73eb5c0c1	-	-	-	-
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Text-mined citations for rs62514952 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000277.3(PAH):c.814G>T (p.Gly272Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62514952 ...