NM_000277.3(PAH):c.931_932del (p.Leu311fs) AND Phenylketonuria

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 14, 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:: RCV000106378.5

Allele description [Variation Report for NM_000277.3(PAH):c.931_932del (p.Leu311fs)]

NM_000277.3(PAH):c.931_932del (p.Leu311fs)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.931_932del (p.Leu311fs)

HGVS:

NC_000012.12:g.102846932AG[2]
NG_008690.2:g.116474CT[2]
NM_000277.3:c.931_932delMANE SELECT
NM_001354304.2:c.931_932del
NP_000268.1:p.Leu311fs
NP_001341233.1:p.Leu311fs
NC_000012.11:g.103240710AG[2]
NC_000012.12:g.102846932_102846933delAG
NM_000277.1:c.931_932delCT
NM_000277.2(PAH):c.931_932delCT
p.Leu311Glyfs

Protein change:

L311fs

Links:

dbSNP: rs281865430

NCBI 1000 Genomes Browser:

rs281865430

Molecular consequence:

NM_000277.3:c.931_932del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354304.2:c.931_932del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000143878	Inserm U 954, Faculté de Médecine de Nancy	no assertion criteria provided	probable-pathogenic	unknown	not provided
SCV001146757	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Jul 14, 2019)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001810553	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000143878

Inserm U 954, Faculté de Médecine de Nancy

no assertion criteria provided

probable-pathogenic

unknown

not provided

SCV001146757

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Pathogenic
(Jul 14, 2019)

germline

curation

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

Citation Link,

SCV001810553

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 22, 2021)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness.

Jeannesson-Thivisol E, Feillet F, Chéry C, Perrin P, Battaglia-Hsu SF, Herbeth B, Cano A, Barth M, Fouilhoux A, Mention K, Labarthe F, Arnoux JB, Maillot F, Lenaerts C, Dumesnil C, Wagner K, Terral D, Broué P, de Parscau L, Gay C, Kuster A, Bédu A, et al.

Orphanet J Rare Dis. 2015 Dec 15;10:158. doi: 10.1186/s13023-015-0375-x.

PubMed [citation]

PMID:: 26666653
PMCID:: PMC5024853

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Inserm U 954, Faculté de Médecine de Nancy, SCV000143878.1

#	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, SCV001146757.1

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

Description

The c.931_932del frameshift variant has been identified in at least 1 proband with mild PKU, BH4 deficiency not excluded (PMID: 26666653). It has been detected in trans with the pathogenic variant R241C (PMID: 26666653). This variant is absent from 1000G, Exac, and gnomAD databases. c.931_932delCT generates a frameshift predicted to result in a premature stop codon 4 residues downstream in exon 9 and undergo NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3_Supporting, PM2, PP4.

#	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

From Genome-Nilou Lab, SCV001810553.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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