VCV000102518.52 - ClinVar

NM_000277.3(PAH):c.1089del (p.Lys363fs)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Phenylketonuria

Classification is based on the expert panel submission

Aug 2018 by ClinGen PAH Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000277.3(PAH):c.1089del (p.Lys363fs)

Variation ID: 102518 Accession: VCV000102518.52

Type and length

Deletion, 1 bp

Location

Cytogenetic: 12q23.2 12: 102843756 (GRCh38) [ NCBI UCSC ] 12: 103237534 (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	Feb 15, 2026	Aug 10, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_000277.3:c.1089del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000268.1:p.Lys363fs	frameshift
NM_000277.3:c.1089delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001354304.2:c.1089del	NP_001341233.1:p.Lys363fs	frameshift
NC_000012.12:g.102843756del
NC_000012.11:g.103237534del
NG_008690.2:g.119655del

... more HGVS ... less HGVS

Protein change

K363fs

Other names

NM_000277.2(PAH):c.1089delG

Canonical SPDI

NC_000012.12:102843755:C:

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), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA229336 dbSNP: rs5030654 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		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	1615	1758

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.
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 31, 2025	RCV000088751.36
Phenylketonuria	Pathogenic (9)	reviewed by expert panel	Aug 10, 2018	RCV000169397.22

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.	Expand all rows Collapse all rows 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) C Contributing to aggregate classification	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Phenylketonuria (Autosomal recessive inheritance)	ClinGen PAH Variant Curation Expert Panel FDA Recognized Database Accession: SCV000852154.4 First in ClinVar: May 03, 2018 Last updated: Dec 11, 2022	Publications: PubMed (1) PubMed: 8659548 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f73ce257-c08b-40ce-845f-012c6403252c Comment: show PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4: Detected in a patient with Classical PKU. (PMID:8659548). 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: (PVS1, PM2, PP4). (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Oct 14, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Phenylketonuria	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696425.1 First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015	Publications: PubMed (2) PubMed: 21147011‚ 8659548 Comment: show Variant summary: The PAH c.1089delG (p.Lys363Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous PKU and HPA patients and is absent in 121252 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 05, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Phenylketonuria	Fulgent Genetics, Fulgent Genetics Accession: SCV002788461.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Phenylketonuria	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002822897.1 First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Nov 03, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Phenylketonuria	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848854.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: show The p.Lys363AsnfsX37 in PAH has been reported in at least 12 homozygous and 1 compound heterozygous individuals affected with Hyperphenylalaninemia or Phenylketonuria (selected publications: Carducci 2020 PMID: 32905092, Zare-Karizi 2011 PMID: 20920871, Kostandyan 2011 PMID: 21890392, Alibakhshi 2014 PMID: 24048906). This variant was classified as Pathogenic on August 10, 2018 by the ClinGen-approved ClinGen PAH Variant Curation Expert Panel (Variation ID 102518) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 363 and leads to a premature termination codon 37 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PAH gene is an established disease mechanism in autosomal recessive Phenylketonuria. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperphenylalanemia/phenylkenonuria. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3_Strong. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 10, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Phenylketonuria	Baylor Genetics Accession: SCV004201365.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Sep 10, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Phenylketonuria	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000943570.6 First in ClinVar: Aug 13, 2019 Last updated: Feb 15, 2026	Publications: PubMed (6) PubMed: 1301187‚ 20920871‚ 21890392‚ 24048906‚ 8889590‚ 9634518 Comment: show This sequence change creates a premature translational stop signal (p.Lys363Asnfs*37) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with phenylketonuria (PMID: 8889590, 20920871, 21890392, 24048906). ClinVar contains an entry for this variant (Variation ID: 102518). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Feb 17, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000568713.5 First in ClinVar: Mar 19, 2014 Last updated: Mar 04, 2023	Comment: show Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9792407, 17096675, 22513348, 8659548, 20920871, 21147011, 9781015, 26481238, 18299955, 28676969, 29499199, 32905092, 31589614, 32778825, 24048906) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

pathogenic (Jul 31, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not provided	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000889561.3 First in ClinVar: Mar 19, 2014 Last updated: Dec 07, 2025	Publications: PubMed (21) PubMed: 17096675‚ 19394257‚ 20920871‚ 21147011‚ 21890392‚ 22513348‚ 24048906‚ 26322415‚ 26481238‚ 26503515‚ 28676969‚ 30389586‚ 31332730‚ 32778825‚ 32905092‚ 33625639‚ 36646061‚ 37189584‚ 8556304‚ 8659548‚ 8889590 Comment: show The PAH c.1089del (p.Lys363Asnfs*37) variant alters the translational reading frame of the PAH mRNA and causes the premature termination of PAH protein synthesis. This variant has been reported in the published literature in homozygous or compound heterozygous individuals affected with Hyperphenylalaninemia or Phenylketonuria (PMIDs: 8659548 (1996), 20920871 (2011), 21147011 (2011), 21890392 (2011), 22513348 (2012), 24048906 (2014), 26322415 (2015), 26503515 (2015), 26481238 (2016), 30389586 (2019), 31332730 (2019), 32905092 (2021), 33625639 (2021), 37189584 (2023). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Jun 01, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001747663.30 First in ClinVar: Jul 10, 2021 Last updated: Jan 11, 2026	Comment: show PAH: PVS1, PM2, PM3:Supporting, PP4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 2

Pathogenic (Sep 16, 2020) N Not contributing to aggregate classification	no assertion criteria provided	Phenylketonuria	Natera, Inc. Accession: SCV001463120.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Oct 14, 2014) N Not contributing to aggregate classification	no assertion criteria provided	Phenylketonuria (Autosomal recessive inheritance)	Counsyl Accession: SCV000220793.3 First in ClinVar: Mar 29, 2015 Last updated: Jul 05, 2025	Publications: PubMed (8) PubMed: 17096675‚ 19394257‚ 20920871‚ 21147011‚ 22513348‚ 24048906‚ 8659548‚ 9781015 Comment: show This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less) Observation: 1 Collection method: literature only Allele origin: unknown Affected status: unknown Observation 1 Collection method: literature only Allele origin: unknown Affected status: unknown

not provided (-) N Not contributing to aggregate classification	no classification provided	not provided	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE Accession: SCV000119335.1 First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014	Observation: 1 Collection method: not provided Allele origin: not provided Affected status: not provided Observation 1 Collection method: not provided Allele origin: not provided Affected status: not provided

Comment:

PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4: Detected in a patient with Classical PKU. (PMID:8659548). 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: (PVS1, PM2, PP4).

Comment:

Variant summary: The PAH c.1089delG (p.Lys363Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous PKU and HPA patients and is absent in 121252 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The p.Lys363AsnfsX37 in PAH has been reported in at least 12 homozygous and 1 compound heterozygous individuals affected with Hyperphenylalaninemia or Phenylketonuria (selected publications: Carducci 2020 PMID: 32905092, Zare-Karizi 2011 PMID: 20920871, Kostandyan 2011 PMID: 21890392, Alibakhshi 2014 PMID: 24048906). This variant was classified as Pathogenic on August 10, 2018 by the ClinGen-approved ClinGen PAH Variant Curation Expert Panel (Variation ID 102518) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 363 and leads to a premature termination codon 37 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PAH gene is an established disease mechanism in autosomal recessive Phenylketonuria. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperphenylalanemia/phenylkenonuria. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3_Strong.

Comment:

This sequence change creates a premature translational stop signal (p.Lys363Asnfs*37) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with phenylketonuria (PMID: 8889590, 20920871, 21890392, 24048906). ClinVar contains an entry for this variant (Variation ID: 102518). For these reasons, this variant has been classified as Pathogenic.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9792407, 17096675, 22513348, 8659548, 20920871, 21147011, 9781015, 26481238, 18299955, 28676969, 29499199, 32905092, 31589614, 32778825, 24048906)

Comment:

The PAH c.1089del (p.Lys363Asnfs*37) variant alters the translational reading frame of the PAH mRNA and causes the premature termination of PAH protein synthesis. This variant has been reported in the published literature in homozygous or compound heterozygous individuals affected with Hyperphenylalaninemia or Phenylketonuria (PMIDs: 8659548 (1996), 20920871 (2011), 21147011 (2011), 21890392 (2011), 22513348 (2012), 24048906 (2014), 26322415 (2015), 26503515 (2015), 26481238 (2016), 30389586 (2019), 31332730 (2019), 32905092 (2021), 33625639 (2021), 37189584 (2023). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
PAH Pathogenic Variants and Clinical Correlations in a Group of Hyperphenylalaninemia Patients from North-Western Romania.	Iuhas A	Diagnostics (Basel, Switzerland)	2023	PMID: 37189584
A Comprehensive Study of Disease-Causing Variants in PAH, QDPR, PTS, and PCD Genes in Iranian Patients with Hyperphenylalaninemia: A Systematic Review.	Ghanei M	Human heredity	2023	PMID: 36646061
Spectrum of PAH gene mutations in 1547 phenylketonuria patients from Iran: a comprehensive systematic review.	Alibakhshi R	Metabolic brain disease	2021	PMID: 33625639
Molecular genetics of phenylketonuria and tetrahydrobiopterin deficiency in Jordan.	Carducci C	JIMD reports	2020	PMID: 32905092
The role of exome sequencing in newborn screening for inborn errors of metabolism.	Adhikari AN	Nature medicine	2020	PMID: 32778825
The study of the full spectrum of variants leading to hyperphenylalaninemia have revealed 10 new variants in the PAH gene.	Kuznetcova I	Metabolic brain disease	2019	PMID: 31332730
A comprehensive study of phenylalanine hydroxylase gene mutations in the Iranian phenylketonuria patients.	Esfahani MS	European journal of medical genetics	2019	PMID: 30389586
Genetic study of the PAH locus in the Iranian population: familial gene mutations and minihaplotypes.	Razipour M	Metabolic brain disease	2017	PMID: 28676969
A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population.	Gemperle-Britschgi C	Gene	2016	PMID: 26481238
Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing.	Li N	Scientific reports	2015	PMID: 26503515
Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria.	Tao J	Pediatric research	2015	PMID: 26322415
Mutation analysis of PAH gene in patients with PKU in western Iran and its association with polymorphisms: identification of four novel mutations.	Alibakhshi R	Metabolic brain disease	2014	PMID: 24048906
Five novel mutations and two large deletions in a population analysis of the phenylalanine hydroxylase gene.	Groselj U	Molecular genetics and metabolism	2012	PMID: 22513348
The spectrum of phenylketonuria genotypes in the Armenian population: identification of three novel mutant PAH alleles.	Kostandyan N	Molecular genetics and metabolism	2011	PMID: 21890392
Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population.	Dobrowolski SF	Molecular genetics and metabolism	2011	PMID: 21147011
Mutation spectrum of phenylketonuria in Iranian population.	Zare-Karizi Sh	Molecular genetics and metabolism	2011	PMID: 20920871
Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency.	Karacić I	Molecular genetics and metabolism	2009	PMID: 19394257
Molecular epidemiology of phenylalanine hydroxylase deficiency in Southern Italy: a 96% detection rate with ten novel mutations.	Daniele A	Annals of human genetics	2007	PMID: 17096675
Mutation at the phenylalanine hydroxylase gene (PAH) and its use to document population genetic variation: the Quebec experience.	Carter KC	European journal of human genetics : EJHG	1998	PMID: 9781015
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
Phenylalanine hydroxylase deficiency in a population in Germany: mutational profile and nine novel mutations.	Guldberg P	Human mutation	1996	PMID: 8889590
Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study.	Guldberg P	American journal of human genetics	1996	PMID: 8659548
Characterization of phenylketonuria alleles in the Italian population.	Dianzani I	European journal of human genetics : EJHG	1995	PMID: 8556304
Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.	Eisensmith RC	Human mutation	1992	PMID: 1301187
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f73ce257-c08b-40ce-845f-012c6403252c	-	-	-	-
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Text-mined citations for rs5030654 ...

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 Feb 15, 2026