NM_000277.3(PAH):c.805A>C (p.Ile269Leu) AND Phenylketonuria

Clinical significance:Pathogenic (Last evaluated: Dec 10, 2018)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
7 submissions [Details]
Record status:
current
Accession:
RCV000281383.14

Allele description [Variation Report for NM_000277.3(PAH):c.805A>C (p.Ile269Leu)]

NM_000277.3(PAH):c.805A>C (p.Ile269Leu)

Gene:
PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q23.2
Genomic location:
Preferred name:
NM_000277.3(PAH):c.805A>C (p.Ile269Leu)
Other names:
NM_000277.1(PAH):c.805A>C
HGVS:
  • NC_000012.12:g.102852852T>G
  • NG_008690.2:g.110559A>C
  • NM_000277.3:c.805A>CMANE SELECT
  • NM_001354304.2:c.805A>C
  • NP_000268.1:p.Ile269Leu
  • NP_001341233.1:p.Ile269Leu
  • NC_000012.11:g.103246630T>G
  • NM_000277.1:c.805A>C
  • P00439:p.Ile269Leu
Protein change:
I269L
Links:
UniProtKB: P00439#VAR_000969; dbSNP: rs62508692
NCBI 1000 Genomes Browser:
rs62508692
Molecular consequence:
  • NM_000277.3:c.805A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.805A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Phenylketonuria (PKU)
Synonyms:
Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
Identifiers:
MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000800539Counsylno assertion criteria providedUncertain significance
(Jan 16, 2019)
unknownclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000827700Invitaecriteria provided, single submitter
Pathogenic
(Aug 26, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000886598ClinGen PAH Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(Dec 10, 2018)
germlinecuration

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000915570Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely pathogenic
(Nov 2, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001362291Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jul 20, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001424211Elsea Laboratory,Baylor College of Medicineno assertion criteria providedLikely pathogenic
(Apr 1, 2020)
germlineclinical testing

SCV001453104Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness.

Bik-Multanowski M, Kaluzny L, Mozrzymas R, Oltarzewski M, Starostecka E, Lange A, Didycz B, Gizewska M, Ulewicz-Filipowicz J, Chrobot A, Mikoluc B, Szymczakiewicz-Multanowska A, Cichy W, Pietrzyk JJ.

Acta Biochim Pol. 2013;60(4):613-6. Epub 2013 Dec 17.

PubMed [citation]
PMID:
24350308

Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases.

Pey AL, Stricher F, Serrano L, Martinez A.

Am J Hum Genet. 2007 Nov;81(5):1006-24. Epub 2007 Oct 2.

PubMed [citation]
PMID:
17924342
PMCID:
PMC2265664
See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000800539.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000827700.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces isoleucine with leucine at codon 269 of the PAH protein (p.Ile269Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs62508692, ExAC 0.03%). This variant has been reported as in combination with another PAH variant in individuals affected with hyperphenylalaninemia (PMID: 9521426, 23500595, 14726806, 21871829). ClinVar contains an entry for this variant (Variation ID: 102842). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen PAH Variant Curation Expert Panel, SCV000886598.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (4)

Description

The c.805A>C (p.Ile269Leu) variant in PAH has been reported in multiple individuals with PAH deficiency, including non-PKU HPA (BH4 deficiency excluded). (PP4_Moderate; PMID10767174, PMID 2350059). This variant has an extremely low allele frequency in ExAC and gnomAD (PM2; ENF=0.00013). This variant was detected in trans with multiple known pathogenic variants: PMID 9521426: c.842+3G>C; PMID 10767174: R261X; PMID 14726806: E280K; PMID 21871829: IVS10-11G>A (PM3_Very-strong). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Very-strong, PP4_Moderate, PM2, PP3.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000915570.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The PAH c.805A>C (p.Ile269Leu) variant has been reported in three studies in which it is found in a total of five individuals, including one sibling pair, with non-phenylketonuria hyperphenylalaninemia (non-PKU HPA). The variant was found in four individuals in a compound heterozygous state and in one individual in cis with a second missense variant and in trans with a third missense variant (Bosco et al. 1998; Rivera et al. 2011; Reblova et al. 2013). Control data are unavailable for the p.Ile269Leu variant which is reported at a frequency of 0.000464 in the Other population of the Genome Aggregation Database. Leandro et al. (2001) showed that the p.Ile269Leu variant caused a moderate reduction in the specific activity of the PAH enzyme as compared to wild type, when expressed in a prokaryotic expression system. Based on the evidence, the p.Ile269Leu variant is classified as likely pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362291.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: PAH c.805A>C (p.Ile269Leu) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251364 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (9.2e-05 vs 0.0079), allowing no conclusion about variant significance. c.805A>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency, including non-PKU hyperphenylalaninemia (e.g. Matalon_2004, Rivera_2011, Couce_2013, Reblova_2013). These data indicate that the variant is very likely to be associated with disease. In vitro studies demonstrated a moderate reduction in residual PAH activity (63%) as compared to wild type (Rivera_2011). Four ClinVar submitters including an expert panel (ClinGen PAH Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic while, one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Elsea Laboratory,Baylor College of Medicine, SCV001424211.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV001453104.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 23, 2021

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