NM_000277.3(PAH):c.806del (p.Ile269fs) AND Phenylketonuria

Clinical significance:Pathogenic (Last evaluated: Aug 10, 2018)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000153633.10

Allele description [Variation Report for NM_000277.3(PAH):c.806del (p.Ile269fs)]

NM_000277.3(PAH):c.806del (p.Ile269fs)

Gene:
PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
12q23.2
Genomic location:
Preferred name:
NM_000277.3(PAH):c.806del (p.Ile269fs)
Other names:
NM_000277.2(PAH):c.806delT
HGVS:
  • NC_000012.12:g.102852851del
  • NG_008690.2:g.110560del
  • NM_000277.3:c.806delMANE SELECT
  • NM_001354304.2:c.806del
  • NP_000268.1:p.Ile269fs
  • NP_001341233.1:p.Ile269fs
  • NC_000012.11:g.103246629del
  • NC_000012.12:g.102852851delA
  • NM_000277.1:c.806del
  • NM_000277.1:c.806delT
  • NM_000277.3:c.806delTMANE SELECT
Protein change:
I269fs
Links:
dbSNP: rs62508687
NCBI 1000 Genomes Browser:
rs62508687
Molecular consequence:
  • NM_000277.3:c.806del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354304.2:c.806del - 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
SCV000485936Counsylno assertion criteria providedLikely pathogenic
(Mar 3, 2016)
unknownclinical testing

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

SCV000629216Invitaecriteria provided, single submitter
Pathogenic
(May 2, 2017)
germlineclinical testing

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

SCV000852125ClinGen PAH Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(Aug 10, 2018)
germlinecuration

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

Citation Link,

SCV001361063Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jun 6, 2019)
germlineclinical testing

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

Citation Link,

SCV001453103Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness.

Ho G, Alexander I, Bhattacharya K, Dennison B, Ellaway C, Thompson S, Wilcken B, Christodoulou J.

JIMD Rep. 2014;14:55-65. doi: 10.1007/8904_2013_284. Epub 2013 Dec 25.

PubMed [citation]
PMID:
24368688
PMCID:
PMC4213336
See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000485936.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000629216.1

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

Description

This sequence change deletes 1 nucleotide from exon 7 of the PAH mRNA (c.806delT), causing a frameshift at codon 269. This creates a premature translational stop signal (p.Ile269Thrfs*72) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic. This particular variant has been reported as homozygous or compound heterozygous in multiple individuals affected with phenylketonuria (PMID: 9012412, 17502162, 23430918, 24368688, 18937047). This variant is also known as 1269fsdelT in the literature. For these reasons, this variant has been classified as Pathogenic.

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

From ClinGen PAH Variant Curation Expert Panel, SCV000852125.3

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

Description

PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency. gnomAD MAF=0.00007.; PP4: Detected in a PKU patient. BH4 deficiency not assessed. (PMID:9012412). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361063.1

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

Description

Variant summary: PAH c.806delT (p.Ile269ThrfsX72) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251364 control chromosomes. c.806delT has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Tyfield_1997, Dombrowolski_2007, Sarkissian_2011, Ho_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories and one expert panel (ClinGen) classify the variant as pathogenic three times and once as likely 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

From Natera, Inc., SCV001453103.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 27, 2021

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