NM_000277.3(PAH):c.1315+2T>C AND Phenylketonuria

Clinical significance:Likely pathogenic (Last evaluated: Dec 9, 2018)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000169029.3

Allele description [Variation Report for NM_000277.3(PAH):c.1315+2T>C]

NM_000277.3(PAH):c.1315+2T>C

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.1315+2T>C
Other names:
NM_000277.2(PAH):c.1315+2T>C
HGVS:
  • NC_000012.12:g.102840398A>G
  • NG_008690.2:g.123013T>C
  • NM_000277.3:c.1315+2T>CMANE SELECT
  • NM_001354304.2:c.1315+2T>C
  • NC_000012.11:g.103234176A>G
  • NM_000277.1:c.1315+2T>C
Links:
dbSNP: rs1799970
NCBI 1000 Genomes Browser:
rs1799970
Molecular consequence:
  • NM_000277.3:c.1315+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354304.2:c.1315+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000220178Counsylcriteria provided, single submitter
Likely pathogenic
(Mar 18, 2014)
unknownliterature only

PubMed (2)
[See all records that cite these PMIDs]

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

Citation Link,

SCV000886570ClinGen PAH Variant Curation Expert Panelreviewed by expert panel
Likely pathogenic
(Dec 9, 2018)
germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001363424Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jan 25, 2019)
germlineclinical testing

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

Citation Link

Summary from all submissions

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

Citations

PubMed

Eight new mutations of the phenylalanine hydroxylase gene in Italian patients with hyperphenylalaninemia.

Bosco P, Cali F, Meli C, Mollica F, Zammarchi E, Cerone R, Vanni C, Palillo L, Greco D, Romano V.

Hum Mutat. 1998;11(3):240-3.

PubMed [citation]
PMID:
9521426

Phenylalanine hydroxylase deficiency in south Italy: Genotype-phenotype correlations, identification of a novel mutant PAH allele and prediction of BH4 responsiveness.

Trunzo R, Santacroce R, D'Andrea G, Longo V, De Girolamo G, Dimatteo C, Leccese A, Bafunno V, Lillo V, Papadia F, Margaglione M.

Clin Chim Acta. 2015 Oct 23;450:51-5. doi: 10.1016/j.cca.2015.07.014. Epub 2015 Jul 23.

PubMed [citation]
PMID:
26210745
See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000220178.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen PAH Variant Curation Expert Panel, SCV000886570.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The c.1315+2T>C variant is at the 3' canonical splice site in the penultimate exon of PAH. It is absent form population databases and has been identified in trans with pathogenic variants in three independent patients (F39del, Y414C, and R261X; PMID: 9452062; 9521426). A defect of BH4 metabolism was excluded as a cause of elevated phenylalanine in all patients. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, 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, SCV001363424.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: PAH c.1315+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. One predict the variant creates/strengthens an alternate cryptic 5' donor site in intron 12. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246184 control chromosomes. c.1315+2T>C has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; Michiels_1998, Mirisola_2001, Trunzo_2015, Vela-Amieva_2015). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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: Aug 27, 2021

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