NM_000277.3(PAH):c.47_48del (p.Leu15_Ser16insTer) 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:
RCV000153638.12

Allele description [Variation Report for NM_000277.3(PAH):c.47_48del (p.Leu15_Ser16insTer)]

NM_000277.3(PAH):c.47_48del (p.Leu15_Ser16insTer)

Gene:
PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
12q23.2
Genomic location:
Preferred name:
NM_000277.3(PAH):c.47_48del (p.Leu15_Ser16insTer)
Other names:
NM_000277.2(PAH):c.47_48delCT
HGVS:
  • NC_000012.12:g.102917083AG[2]
  • NG_008690.2:g.46323CT[2]
  • NM_000277.3:c.47_48delMANE SELECT
  • NM_001354304.2:c.47_48del
  • NP_000268.1:p.Leu15_Ser16insTer
  • NP_001341233.1:p.Leu15_Ser16insTer
  • NC_000012.11:g.103310861AG[2]
  • NC_000012.12:g.102917083_102917084delAG
  • NM_000277.1:c.47_48del
  • NM_000277.1:c.47_48delCT
  • NM_000277.3:c.47_48delCTMANE SELECT
Links:
dbSNP: rs62642906
NCBI 1000 Genomes Browser:
rs62642906
Molecular consequence:
  • NM_000277.3:c.47_48del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354304.2:c.47_48del - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000221085Counsylcriteria provided, single submitter
Likely pathogenic
(Jan 26, 2015)
unknownliterature only

PubMed (11)
[See all records that cite these PMIDs]

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

Citation Link,

SCV000754077Invitaecriteria provided, single submitter
Pathogenic
(Sep 30, 2017)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000852108ClinGen PAH Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(Aug 10, 2018)
germlinecuration

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

Citation Link,

SCV001362289Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Mar 25, 2019)
germlineclinical testing

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

Citation Link,

SCV001459232Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

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

A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin.

Dobrowolski SF, Borski K, Ellingson CC, Koch R, Levy HL, Naylor EW.

J Hum Genet. 2009 Jun;54(6):335-9. doi: 10.1038/jhg.2009.37. Epub 2009 May 15.

PubMed [citation]
PMID:
19444284

Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.

Zurflüh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N.

Hum Mutat. 2008 Jan;29(1):167-75.

PubMed [citation]
PMID:
17935162
See all PubMed Citations (16)

Details of each submission

From Counsyl, SCV000221085.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (11)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000754077.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Ser16*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs62642906, ExAC 0.001%). This variant has been reported in several individuals affected with hyperphenylalaninemia and phenylketonuria (PMID: 8535445, 10394930, 16198137, 17096675, 21147011, 21890392, 26322415). This variant is also known as c.44_45delTC, p.Ser16fs in the literature. ClinVar contains an entry for this variant (Variation ID: 102696). 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

From ClinGen PAH Variant Curation Expert Panel, SCV000852108.3

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

Description

PAH-specific ACMG/AMP criteria applied: PM2: ExAC:8.238e-06; gnomAD:0.000004062; 1000G + ESP: absent; PVS1: Null variant- frameshift. Subject to nonsense mediated decay.; PM3: found in trans with L48S (VarID608, Pathogenic) (PMID:8535445); PP4: 47delCT found in 1 patient with moderate PKU. BH4 deficiency not ruled out. (PMID:8535445). 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: (PM2, PVS1, PM3, 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, SCV001362289.1

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

Description

Variant summary: PAH c.47_48delCT (p.Ser16X) 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 (c.165delT, p.Phe55fsX6; c.331C>T, p.Arg111X; c.556delA, p.Thr186fsX9). The variant allele was found at a frequency of 4.1e-06 in 246214 control chromosomes (gnomAD). This variant has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Aldamiz-Echevarria_2016, Ramus_1995, Tao_2015, Trunzo_2015, Wang_2017). These data indicate that the variant is very likely to be associated with disease. In vitro expression experiment reports that PAH residual activity for this variant effect results in <10% of normal activity (Aldamiz-Echevarria_2016). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/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., SCV001459232.1

#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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