NM_000277.3(PAH):c.500A>T (p.Asn167Ile) AND Phenylketonuria

Clinical significance:Likely pathogenic (Last evaluated: Aug 28, 2018)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000412232.9

Allele description [Variation Report for NM_000277.3(PAH):c.500A>T (p.Asn167Ile)]

NM_000277.3(PAH):c.500A>T (p.Asn167Ile)

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.500A>T (p.Asn167Ile)
Other names:
NM_000277.2(PAH):c.500A>T
HGVS:
  • NC_000012.12:g.102866605T>A
  • NG_008690.2:g.96806A>T
  • NM_000277.3:c.500A>TMANE SELECT
  • NM_001354304.2:c.500A>T
  • NP_000268.1:p.Asn167Ile
  • NP_001341233.1:p.Asn167Ile
  • NC_000012.11:g.103260383T>A
  • NM_000277.1:c.500A>T
  • P00439:p.Asn167Ile
Protein change:
N167I
Links:
UniProtKB: P00439#VAR_000906; dbSNP: rs77554925
NCBI 1000 Genomes Browser:
rs77554925
Molecular consequence:
  • NM_000277.3:c.500A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.500A>T - 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
SCV000485290Counsylcriteria provided, single submitter
Likely pathogenic
(Dec 29, 2015)
unknownclinical testing

PubMed (11)
[See all records that cite these PMIDs]

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV000830097Invitaecriteria provided, single submitter
Pathogenic
(Oct 29, 2020)
germlineclinical testing

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

SCV000852095ClinGen PAH Variant Curation Expert Panelreviewed by expert panel
Likely pathogenic
(Aug 28, 2018)
germlinecuration

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

Citation Link,

SCV001623309Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Apr 20, 2021)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation.

Mallolas J, Vilaseca MA, Campistol J, Lambruschini N, Cambra FJ, Estivill X, Milà M.

Hum Genet. 1999 Nov;105(5):468-73.

PubMed [citation]
PMID:
10598814

6R-tetrahydrobiopterin treated PKU patients below 4 years of age: Physical outcomes, nutrition and genotype.

Aldámiz-Echevarría L, Bueno MA, Couce ML, Lage S, Dalmau J, Vitoria I, Llarena M, Andrade F, Blasco J, Alcalde C, Gil D, García MC, González-Lamuño D, Ruiz M, Ruiz MA, Peña-Quintana L, González D, Sánchez-Valverde F.

Mol Genet Metab. 2015 May;115(1):10-6. doi: 10.1016/j.ymgme.2015.03.007. Epub 2015 Apr 1.

PubMed [citation]
PMID:
25882749
See all PubMed Citations (13)

Details of each submission

From Counsyl, SCV000485290.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000830097.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces asparagine with isoleucine at codon 167 of the PAH protein (p.Asn167Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is present in population databases (rs77554925, ExAC 0.003%). This variant has been reported in combination with another PAH variant in several individuals affected with PKU or HPA (PMID: 9452062, 10234516, 26666653, 24368688, 23430918, 22112818, Invitae), being reported on the opposite chromosome (in trans) from other pathogenic variant in an individual affected with carnitine deficiency (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 92743). Experimental studies have shown that this missense change does not have an effect on the enzyme catalytic kinetics; however, authors pointed out that this variant causes the protein to aggregate so its effect may be in misfolding (PMID: 12554741). 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, SCV000852095.3

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

Description

PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (MAF=0.00003). Absent from gnomAD, 1000G, ESP; PP4_Moderate: Found in a French patient with HPA and 2 unrelated UK patients. BH4 deficiencies not assessed/reported. Seen in 1 German patient, Cofactor deficiency was excluded by the BH4 test. 1 Spanish patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. (PMID:26666653; PMID:9012412; PMID:10679941); PM3_Strong: Patient 664 with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants. (PMID:24368688; PMID:26666653). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623309.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: PAH c.500A>T (p.Asn167Ile) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251360 control chromosomes. c.500A>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; e.g. Tyfield_1997, Desviat_1999, Utz_2011, Jeannesson-Thivisol_2015). These data indicate that the variant is very likely to be associated with disease. A functional study investigating the variant effects in E. coli reported that the variant did not appear to significantly alter the kinetic properties of the enzyme, but suggested that it may de-stabilize the secondary structure of the protein, resulting in aggregation (e.g. Carvalho_2003). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance (n=1) and pathogenic/likely pathogenic (n=3). 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

Last Updated: Sep 12, 2021

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