NM_000277.3(PAH):c.350del (p.Thr117fs) AND Phenylketonuria

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 22, 2018
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:: RCV000106355.3

Allele description [Variation Report for NM_000277.3(PAH):c.350del (p.Thr117fs)]

NM_000277.3(PAH):c.350del (p.Thr117fs)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.350del (p.Thr117fs)

HGVS:

NC_000012.12:g.102894737del
NG_008690.2:g.68674del
NM_000277.3:c.350delMANE SELECT
NM_001354304.2:c.350del
NP_000268.1:p.Thr117fs
NP_001341233.1:p.Thr117fs
NC_000012.11:g.103288515del
NC_000012.12:g.102894737delG
NM_000277.1:c.350delC
NM_000277.2(PAH):c.350delC
p.Thr117Lysfs

Protein change:

T117fs

Links:

dbSNP: rs281865428

NCBI 1000 Genomes Browser:

rs281865428

Molecular consequence:

NM_000277.3:c.350del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354304.2:c.350del - 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

Recent activity

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neuronal calcium sensor 1 [Rattus norvegicus]
neuronal calcium sensor 1 [Rattus norvegicus]
gi|13242261|ref|NP_077342.1|

Protein
Homo sapiens solute carrier family 35, member B2, mRNA (cDNA clone IMAGE:3888869...
Homo sapiens solute carrier family 35, member B2, mRNA (cDNA clone IMAGE:3888869), partial cds
gi|16877135|gb|BC016839.1|

Nucleotide
Chain A, FRUCTOSE-1,6-BISPHOSPHATASE
Chain A, FRUCTOSE-1,6-BISPHOSPHATASE
gi|1311146|pdb|1FTA|A

Protein
52 kDa repressor of the inhibitor of the protein kinase isoform X2 [Mus musculus...
52 kDa repressor of the inhibitor of the protein kinase isoform X2 [Mus musculus]
gi|1907184370|ref|XP_036009360.1|

Protein
deoxyguanosinetriphosphate triphosphohydrolase [Acetivibrio thermocellus]
deoxyguanosinetriphosphate triphosphohydrolase [Acetivibrio thermocellus]
gi|490598385|ref|WP_004463405.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000143854	Inserm U 954, Faculté de Médecine de Nancy	no assertion criteria provided	probable-pathogenic	unknown	not provided
SCV001146721	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Dec 22, 2018)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 18294361, 18299955 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000143854

Inserm U 954, Faculté de Médecine de Nancy

no assertion criteria provided

probable-pathogenic

unknown

not provided

SCV001146721

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Pathogenic
(Dec 22, 2018)

germline

curation

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

A mutation analysis of the phenylalanine hydroxylase (PAH) gene in the Israeli population.

Bercovich D, Elimelech A, Yardeni T, Korem S, Zlotogora J, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y.

Ann Hum Genet. 2008 May;72(Pt 3):305-9. doi: 10.1111/j.1469-1809.2007.00425.x. Epub 2008 Feb 19.

PubMed [citation]

PMID:: 18294361

Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene.

Bercovich D, Elimelech A, Zlotogora J, Korem S, Yardeni T, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y.

J Hum Genet. 2008;53(5):407-418. doi: 10.1007/s10038-008-0264-4. Epub 2008 Feb 26.

PubMed [citation]

PMID:: 18299955

Details of each submission

From Inserm U 954, Faculté de Médecine de Nancy, SCV000143854.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

Description

Converted during submission to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen PAH Variant Curation Expert Panel, SCV001146721.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

The c.350delC variant in PAH has been previously reported in at least 2 Arab-Israeli probands with classic PKU (PMID: 18299955; PMID: 18294361); BH4 deficiency was not excluded (PP4). The variant is a frameshift variant occurring in exon 3 of 13 in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (PVS1; see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and the Greater Middle East Variome (PM2).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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