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

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Mar 26, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000350592.21

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

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

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>C

HGVS:

NC_000012.12:g.102912786C>G
NG_008690.2:g.50625G>C
NM_000277.3:c.168+5G>CMANE SELECT
NM_001354304.2:c.168+5G>C
NC_000012.11:g.103306564C>G
NM_000277.1:c.168+5G>C

Links:

dbSNP: rs62507288

NCBI 1000 Genomes Browser:

rs62507288

Molecular consequence:

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

Recent activity

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AAP33703 (0)
Conserved Domains
RNA polymerase subunit sigma-24 [Enterobacter ludwigii]
RNA polymerase subunit sigma-24 [Enterobacter ludwigii]
gi|1072800303|gnl|PRJNA343411|BH714 0|gb|AOT46174.1|

Protein
JGI_XZT31581.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7607905 5'...
JGI_XZT31581.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7607905 5', mRNA sequence
gi|74087170|gnl|dbEST|31252544|gb|C 11.2|

Nucleotide
daj35g10.y1 NICHD_XGC_OO1 Xenopus laevis cDNA clone IMAGE:5078587 5' similar to ...
daj35g10.y1 NICHD_XGC_OO1 Xenopus laevis cDNA clone IMAGE:5078587 5' similar to TR:Q9W0B4 Q9W0B4 CG13920 PROTEIN, mRNA sequence
gi|16439485|gnl|dbEST|10021807|gb|B 11.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000789326	Counsyl	no assertion criteria provided	Pathogenic (Feb 1, 2017)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26666653, 26600521, 22526846, 24048906
SCV000919912	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 6, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20920871, 23856132, 20082265 Citation Link,
SCV000951830	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8364593, 21890392, 22330942, 22526846, 17576681, 9536098, 28492532
SCV001138804	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV002088675	Natera, Inc.	no assertion criteria provided	Pathogenic (Jul 17, 2020)	germline	clinical testing
SCV004201375	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 17, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004807223	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848751	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 26, 2022)	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	unknown	unknown	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	clinical testing

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

Prenatal diagnosis of Chinese families with phenylketonuria.

Liu N, Kong XD, Zhao DH, Wu QH, Li XL, Guo HF, Cui LX, Jiang M, Shi HR.

Genet Mol Res. 2015 Nov 19;14(4):14615-28. doi: 10.4238/2015.November.18.25.

PubMed [citation]

PMID:: 26600521

See all PubMed Citations (14)

Details of each submission

From Counsyl, SCV000789326.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919912.1

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

Description

Variant summary: PAH c.168+5G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predicts the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-05 in 121372 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4.1e-05 vs 0.0079), allowing no conclusion about variant significance. c.168+5G>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), including numerous homozygous patients. These data indicate that the variant is very likely to be associated with disease. In addition, two overlapping variants (c.168+5G>T and c.168+5G>A) have been reported in patients, suggesting any change to this nucleotide may result in disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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, SCV000951830.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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. This variant is present in population databases (rs62507288, gnomAD 0.007%). This variant has been observed in individuals with hyperphenylalaninemia or phenylketonuria (PMID: 8364593, 21890392, 22330942, 22526846). ClinVar contains an entry for this variant (Variation ID: 102606). 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. For these reasons, this variant has been classified as Pathogenic.

#	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 Mendelics, SCV001138804.1

#	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 Natera, Inc., SCV002088675.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004201375.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004807223.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848751.1

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

Description

The c.168+5G>C (IVS2+5G>C) variant in PAH has been reported in at least 44 individuals with phenylalanine hydroxylase deficiency/phenylketonuria (PKU)/hyperphenylalaninemia (HPA) (Zygulska 1993 PMID: 8364593, Zare-Karizi 2011 PMID: 20920871, Sterl 2013 PMID: 22526846, Santos 2010 PMID: 20082265, Muras 2013 PMID: 23856132, Georgiou 2012 PMID: 22330942, Ferreira 2021 PMID: 33465300, Alibakhshi 2014 PMID: 24048906), including at least 20 homozygous individuals and 24 compound heterozygous individuals for a second pathogenic variant in PAH. It has been identified in 0.00006% of NFE chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID: 102606). This variant is located just outside of the concensus splice sequence and computational splice prediction tools predict a splicing impact, though this information is not predictive enough to determine/rule out pathogenicity. This variant occurs in intron 2 of PAH where additional pathogenic variants have been identifed, including at the same base pair (c.168+5G>A, c.168+5G>T). In summary, c.168+5G>C (IVS2+2G>C ) meets the criteria to be classified as pathogenic for autosomal recessive PKU. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, 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

Last Updated: Oct 20, 2024

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