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NM_000277.3(PAH):c.266_267insG (p.Ala90fs) AND Phenylketonuria

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 4, 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:
RCV000993633.1

Allele description [Variation Report for NM_000277.3(PAH):c.266_267insG (p.Ala90fs)]

NM_000277.3(PAH):c.266_267insG (p.Ala90fs)

Gene:
PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]
Variant type:
Insertion
Cytogenetic location:
12q23.2
Genomic location:
Preferred name:
NM_000277.3(PAH):c.266_267insG (p.Ala90fs)
HGVS:
  • NC_000012.12:g.102894820_102894821insC
  • NG_008690.2:g.68590_68591insG
  • NM_000277.3:c.266_267insGMANE SELECT
  • NM_001354304.2:c.266_267insG
  • NP_000268.1:p.Ala90fs
  • NP_001341233.1:p.Ala90fs
  • NC_000012.11:g.103288598_103288599insC
Protein change:
A90fs
Links:
dbSNP: rs1592978760
NCBI 1000 Genomes Browser:
rs1592978760
Molecular consequence:
  • NM_000277.3:c.266_267insG - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354304.2:c.266_267insG - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001146765ClinGen PAH Variant Curation Expert Panel
reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)
Pathogenic
(Apr 4, 2019)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study.

Burton BK, Grange DK, Milanowski A, Vockley G, Feillet F, Crombez EA, Abadie V, Harding CO, Cederbaum S, Dobbelaere D, Smith A, Dorenbaum A.

J Inherit Metab Dis. 2007 Oct;30(5):700-7. Epub 2007 Sep 12.

PubMed [citation]
PMID:
17846916

Details of each submission

From ClinGen PAH Variant Curation Expert Panel, SCV001146765.1

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

Description

The c.266_267insG variant in PAH has been previously reported as a homozygous variant in an Australian proband with PKU (not otherwise specified) from a consanguineous family; the paper does not state whether BH4 deficiency was excluded (PMID: 24368688). The variant was also found in a French proband with classic PKU in trans with the p.Pro281Leu variant, which has been classified as a VUS per internal PAH ClinGen Working Group classification (see PAH0660); the paper does not state whether BH4 deficiency was excluded (PMID: 26666653). The variant was also found in 1 Caucasian proband with classic PKU, in trans with the known pathogenic c.1066-11G>A variant (PMID: 23430918); BH4 deficiency was excluded via biochemical testing per the recruiting study protocol (PMID: 17846916). Finally, it was found in three Southern German probands with classic PKU; no further details regarding genotype and/or exclusion of BH4 deficiency were given (PMID: 12655553). Thus, PP4_Moderate and PM3 apply per the report in PMID: 17846916. The sequence change results in a frameshift variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate.

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

Last Updated: Apr 23, 2022