NM_000277.3(PAH):c.1066-3C>T AND Phenylketonuria

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Sep 26, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000000654.13

Allele description [Variation Report for NM_000277.3(PAH):c.1066-3C>T]

NM_000277.3(PAH):c.1066-3C>T

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.1066-3C>T
HGVS:
  • NC_000012.12:g.102843782G>A
  • NG_008690.2:g.119629C>T
  • NM_000277.3:c.1066-3C>TMANE SELECT
  • NM_001354304.2:c.1066-3C>T
  • NC_000012.11:g.103237560G>A
  • NM_000277.1:c.1066-3C>T
Note:
NCBI staff reviewed the sequence information reported in PubMed 8098245 Fig. 2 determine the location of this allele on the current reference sequence.
Nucleotide change:
IVS10AS, C-T, -3
Links:
OMIM: 612349.0049; dbSNP: rs62507344
NCBI 1000 Genomes Browser:
rs62507344
Molecular consequence:
  • NM_000277.3:c.1066-3C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354304.2:c.1066-3C>T - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000020804OMIMno assertion criteria providedPathogenic
(Jan 1, 1993)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000220862Counsylcriteria provided, single submitter
Likely pathogenic
(Nov 6, 2014)
unknownliterature only

PubMed (16)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000836557Invitaecriteria provided, single submitter
Pathogenic
(Sep 26, 2020)
germlineclinical testing

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

SCV000914555Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Pathogenic
(Dec 18, 2018)
germlineclinical testing

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

Citation Link,

SCV001362284Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(May 13, 2019)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Phenylketonuria mutation analysis in Northern Ireland: a rapid stepwise approach.

Zschocke J, Graham CA, Carson DJ, Nevin NC.

Am J Hum Genet. 1995 Dec;57(6):1311-7.

PubMed [citation]
PMID:
8533759
PMCID:
PMC1801432

Utility of phenylalanine hydroxylase genotype for tetrahydrobiopterin responsiveness classification in patients with phenylketonuria.

Quirk ME, Dobrowolski SF, Nelson BE, Coffee B, Singh RH.

Mol Genet Metab. 2012 Sep;107(1-2):31-6. doi: 10.1016/j.ymgme.2012.07.008. Epub 2012 Jul 20.

PubMed [citation]
PMID:
22841515
PMCID:
PMC4029439
See all PubMed Citations (20)

Details of each submission

From OMIM, SCV000020804.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a French patient with a mild form of phenylketonuria (PKU; 261600), Abadie et al. (1993) found deletion of exon 11 due to a C-to-T transition at the first nucleotide of the splice acceptor triplet of intron 10. The mother was heterozygous for the mutation. The other allele was the R261Q mutation (612349.0006), which has also been associated with mild phenylketonuria and in this case was inherited from the father.

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

From Counsyl, SCV000220862.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (16)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000836557.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This sequence change falls in intron 10 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs62507344, ExAC 0.02%). This variant has been observed as homozygous in individuals affected with mild hyperphenylalaninemia or in combination with other pathogenic variants in several individuals affected with mild hyperphenylalaninemia and phenylketonuria (PMID: 8098245, 17502162, 19444284, 22526846, 22698810, 23357515 , 24368688, 26666653). 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: 623). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change leads to the out-of-frame skipping of exon 11 (PMID: 8098245, 22698810). For these reasons, this variant has been classified as Pathogenic.

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

From Illumina Clinical Services Laboratory,Illumina, SCV000914555.1

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

Description

Across a selection of the available literature, the PAH c.1066-3C>T splice region variant has been reported in at least six studies in which it is found in a total of 15 probands including one in a homozygous state and 14 in a compound heterozygous state (Abadie et al. 1993; Dobrowolski et al. 2009; Heintz et al. 2012; Sterl et al. 2013; Ho et al. 2014; Jeannesson-Thivisol et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (Finnish) population of the Genome Aggregation Database. Liver biopsy from a compound heterozygous proband found 1.5% of normal PAH activity (Abadie et al. 1993). RT-PCR of proband derived lymphoblast cells indicated exon 11 skipping and COS-1 cells transfected with minigenes confirmed c.1066-3C>T as the cause of exon 11 skipping (Heintz et al. 2012). Based on the evidence, the c.1066-3C>T variant is classified as 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, SCV001362284.1

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

Description

Variant summary: PAH c.1066-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3' acceptor site and two predict the variant weakens a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to exon 11 skipping (Heintz_2012). The variant allele was found at a frequency of 4e-05 in 250904 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4e-05 vs 0.0079), allowing no conclusion about variant significance. c.1066-3C>T has been reported in the literature in multiple individuals affected with Phenylketonuria and Hyperphenylalaninemia (Heintz_2012, Reblova_2013, Sterl_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. 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 6, 2021

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