NM_000277.3(PAH):c.168+5G>A AND Phenylketonuria

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: May 26, 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:: RCV000666582.5

Allele description [Variation Report for NM_000277.3(PAH):c.168+5G>A]

NM_000277.3(PAH):c.168+5G>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.168+5G>A

HGVS:

NC_000012.12:g.102912786C>T
NG_008690.2:g.50625G>A
NM_000277.3:c.168+5G>AMANE SELECT
NM_001354304.2:c.168+5G>A
NC_000012.11:g.103306564C>T
NM_000277.1:c.168+5G>A
NM_000277.2(PAH):c.168+5G>A

Links:

dbSNP: rs62507288

NCBI 1000 Genomes Browser:

rs62507288

Molecular consequence:

NM_000277.3:c.168+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354304.2:c.168+5G>A - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000790893	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (May 15, 2018)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9429153, 27121329, 26413448, 23690520, 18798839 Citation Link,
SCV001138805	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001146713	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (May 26, 2019)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 26413448, 9429153, 27121329 Citation Link,
SCV004296193	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 26, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 17576681, 9536098, 9429153, 29288420, 33465300, 8364593, 21890392, 22330942, 22526846, 28492532

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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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study.

Keil S, Anjema K, van Spronsen FJ, Lambruschini N, Burlina A, Bélanger-Quintana A, Couce ML, Feillet F, Cerone R, Lotz-Havla AS, Muntau AC, Bosch AM, Meli CA, Billette de Villemeur T, Kern I, Riva E, Giovannini M, Damaj L, Leuzzi V, Blau N.

Pediatrics. 2013 Jun;131(6):e1881-8. doi: 10.1542/peds.2012-3291. Epub 2013 May 20.

PubMed [citation]

PMID:: 23690520

PKU in Minas Gerais State, Brazil: mutation analysis.

Santos LL, Castro-Magalhães M, Fonseca CG, Starling AL, Januário JN, Aguiar MJ, Carvalho MR.

Ann Hum Genet. 2008 Nov;72(Pt 6):774-9. doi: 10.1111/j.1469-1809.2008.00476.x. Epub 2008 Sep 16.

PubMed [citation]

PMID:: 18798839

See all PubMed Citations (14)

Details of each submission

From Counsyl, SCV000790893.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

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

From Mendelics, SCV001138805.1

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

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

From ClinGen PAH Variant Curation Expert Panel, SCV001146713.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

The c.168+5G>A variant has been identified in at least 4 probands with phenotypes ranging from mild HPA to classic PKU, with at least 2 probands excluding BH4 deficiency (PMIDs: 9429153, 26413448, 27121329). It has been detected in the homozygous form (PMID: 26413448) as well as in trans with pathogenic variants R297H (PMID: 9429153), I65T, and S349P (PMID: 27121329). This variant is absent from 1000G, ESP, and gnomAD databases. Computational analysis predicts an alteration of the WT donor site, most probably affecting splicing. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate, PP3.

#	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, SCV004296193.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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: 102605). This variant is also known as IVS2+5G>A. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 9429153, 29288420, 33465300). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. It affects a nucleotide within the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.168+5G nucleotide in the PAH gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8364593, 21890392, 22330942, 22526846). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing.

#	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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