NM_000277.3(PAH):c.970-1G>A AND Phenylketonuria

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Apr 30, 2020
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:: RCV000106379.5

Allele description [Variation Report for NM_000277.3(PAH):c.970-1G>A]

NM_000277.3(PAH):c.970-1G>A

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.970-1G>A

HGVS:

NC_000012.12:g.102844432C>T
NG_008690.2:g.118979G>A
NM_000277.3:c.970-1G>AMANE SELECT
NM_001354304.2:c.970-1G>A
NC_000012.11:g.103238210C>T
NC_000012.11:g.103238210C>T
NM_000277.1:c.970-1G>A
NM_000277.3(PAH):c.970-1G>AMANE SELECT

Links:

dbSNP: rs202183605

NCBI 1000 Genomes Browser:

rs202183605

Molecular consequence:

NM_000277.3:c.970-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354304.2:c.970-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000143879	Inserm U 954, Faculté de Médecine de Nancy	no assertion criteria provided	probable-pathogenic	unknown	not provided
SCV001370829	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Apr 30, 2020)	germline	curation	Citation Link,
SCV004373529	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 15, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 28676969, 32668217, 16199547, 1301187, 9634518, 28492532 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000143879

Inserm U 954, Faculté de Médecine de Nancy

no assertion criteria provided

probable-pathogenic

unknown

not provided

SCV001370829

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Likely pathogenic
(Apr 30, 2020)

germline

curation

Citation Link,

SCV004373529

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 15, 2023)

germline

clinical testing

PubMed (6)
[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	clinical testing, curation
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Genetic study of the PAH locus in the Iranian population: familial gene mutations and minihaplotypes.

Razipour M, Alavinejad E, Sajedi SZ, Talebi S, Entezam M, Mohajer N, Kazemi-Sefat GE, Gharesouran J, Setoodeh A, Mohaddes Ardebili SM, Keramatipour M.

Metab Brain Dis. 2017 Oct;32(5):1685-1691. doi: 10.1007/s11011-017-0048-7. Epub 2017 Jul 4.

PubMed [citation]

PMID:: 28676969

The Genetic Landscape and Epidemiology of Phenylketonuria.

Hillert A, Anikster Y, Belanger-Quintana A, Burlina A, Burton BK, Carducci C, Chiesa AE, Christodoulou J, Đorđević M, Desviat LR, Eliyahu A, Evers RAF, Fajkusova L, Feillet F, Bonfim-Freitas PE, Giżewska M, Gundorova P, Karall D, Kneller K, Kutsev SI, Leuzzi V, Levy HL, et al.

Am J Hum Genet. 2020 Aug 6;107(2):234-250. doi: 10.1016/j.ajhg.2020.06.006. Epub 2020 Jul 14.

PubMed [citation]

PMID:: 32668217
PMCID:: PMC7413859

See all PubMed Citations (6)

Details of each submission

From Inserm U 954, Faculté de Médecine de Nancy, SCV000143879.1

#	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, SCV001370829.1

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

Description

The c.970-1G>A variant in PAH is a splice-site variant predicted to result in skipping of exon 10, which is a key region of the encoded enzyme (PVS1_Strong). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is reported Likely Pathogenic for PKU in Clinvar by a single lab (ID 120298), without further information. It has also been reported in the BioPKU database as an online submission in 2013, without further information. Classification: Likely Pathogenic Supporting ACMG criteria: PVS1_Strong, 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004373529.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 120298). Disruption of this splice site has been observed in individual(s) with hyperphenylalaninemia (PMID: 28676969, 32668217; BIOPKU http://www.biopku.org). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518).

#	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: Sep 29, 2024

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