NM_000277.3(PAH):c.1099del (p.Leu367fs) AND Phenylketonuria

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Dec 13, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000781680.3

Allele description [Variation Report for NM_000277.3(PAH):c.1099del (p.Leu367fs)]

NM_000277.3(PAH):c.1099del (p.Leu367fs)

Gene:
PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
12q23.2
Genomic location:
Preferred name:
NM_000277.3(PAH):c.1099del (p.Leu367fs)
HGVS:
  • NC_000012.12:g.102843750del
  • NG_008690.2:g.119665del
  • NM_000277.3:c.1099delMANE SELECT
  • NM_001354304.2:c.1099del
  • NP_000268.1:p.Leu367fs
  • NP_001341233.1:p.Leu367fs
  • NC_000012.11:g.103237524del
  • NC_000012.11:g.103237528del
  • NM_000277.1:c.1099del
  • NM_000277.1:c.1099delC
Protein change:
L367fs
Links:
dbSNP: rs62506951
NCBI 1000 Genomes Browser:
rs62506951
Molecular consequence:
  • NM_000277.3:c.1099del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354304.2:c.1099del - 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
SCV000919922Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Aug 27, 2018)
germlineclinical testing

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

Citation Link,

SCV001199465Invitaecriteria provided, single submitter
Pathogenic
(Dec 13, 2019)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria.

Wettstein S, Underhaug J, Perez B, Marsden BD, Yue WW, Martinez A, Blau N.

Eur J Hum Genet. 2015 Mar;23(3):302-9. doi: 10.1038/ejhg.2014.114. Epub 2014 Jun 18.

PubMed [citation]
PMID:
24939588
PMCID:
PMC4326710

[The mutation spectrum of phenylalanine hydroxylase gene in patients with phenylketonuria in Henan province].

Wang FY, Shao CJ, Feng HG, Li CM.

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2010 Dec;27(6):644-9. doi: 10.3760/cma.j.issn.1003-9406.2010.06.009. Chinese.

PubMed [citation]
PMID:
21154324
See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919922.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: PAH c.1099delC (p.Leu367TrpfsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 245994 control chromosomes. c.1099delC has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic.

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

From Invitae, SCV001199465.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Leu367Trpfs*33) in the PAH gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with phenylketonuria (PMID: 29176022, 29499199). ClinVar contains an entry for this variant (Variation ID: 102524). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Jun 14, 2021

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