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NM_000277.3(PAH):c.168+2T>C AND Phenylketonuria

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 9, 2019
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000993645.1

Allele description [Variation Report for NM_000277.3(PAH):c.168+2T>C]

NM_000277.3(PAH):c.168+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.168+2T>C
HGVS:
  • NC_000012.12:g.102912789A>G
  • NG_008690.2:g.50622T>C
  • NM_000277.3:c.168+2T>CMANE SELECT
  • NM_001354304.2:c.168+2T>C
  • NC_000012.11:g.103306567A>G
  • NM_001354304.1:c.168+2T>C
Links:
dbSNP: rs1025860114
NCBI 1000 Genomes Browser:
rs1025860114
Molecular consequence:
  • NM_000277.3:c.168+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354304.2:c.168+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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001146777ClinGen PAH Variant Curation Expert Panel
reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)		Pathogenic
(Apr 9, 2019) 		germlinecuration

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

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Spectrum of PAH gene variants among a population of Han Chinese patients with phenylketonuria from northern China.

Liu N, Huang Q, Li Q, Zhao D, Li X, Cui L, Bai Y, Feng Y, Kong X.

BMC Med Genet. 2017 Oct 5;18(1):108. doi: 10.1186/s12881-017-0467-7. Erratum in: BMC Med Genet. 2018 Jan 9;19(1):6. doi: 10.1186/s12881-017-0516-2.

PubMed [citation]
PMID:
28982351
PMCID:
PMC5629770

Details of each submission

From ClinGen PAH Variant Curation Expert Panel, SCV001146777.1

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

Description

The c.168+2T>C variant in PAH was reported in one patient with PKU (BH4 deficiency excluded) in trans with p.R243Q (PP4_Moderate, PM3; PMID: 28982351). This variant is absent from population databases, including gnomAD (PM2). This variant occurs at a canonical splice site, which will result in abnormal splicing at the donor site of intron 2 where LOF is a known mechanism of disease, exon skipping preserves reading frame, but the altered region is critical to protein function (14 non-truncating pathogenic variants in the region). (PVS1_strong). In summary, this variant meets the criteria to be classified pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PVS1_strong, PM2, PM3.

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

Last Updated: Jun 10, 2023