NM_000277.3(PAH):c.1066-11G>A AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Jul 19, 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:: RCV000078500.46

Allele description [Variation Report for NM_000277.3(PAH):c.1066-11G>A]

NM_000277.3(PAH):c.1066-11G>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.1066-11G>A

Other names:

IVS10-11G>A; NM_000277.1(PAH):c.1066-11G>A

HGVS:

NC_000012.12:g.102843790C>T
NG_008690.2:g.119621G>A
NM_000277.3:c.1066-11G>AMANE SELECT
NM_001354304.2:c.1066-11G>A
NC_000012.11:g.103237568C>T
NM_000277.1:c.1066-11G>A
NM_001354304.1:c.1066-11G>A
c.1066-11G>A (p.?)

Nucleotide change:

IVS10AS, G-A, -11

Links:

OMIM: 612349.0033; dbSNP: rs5030855

NCBI 1000 Genomes Browser:

rs5030855

Molecular consequence:

NM_000277.3:c.1066-11G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354304.2:c.1066-11G>A - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Vibrio mimicus strain FDAARGOS_112 chromosome 1, complete sequence
Vibrio mimicus strain FDAARGOS_112 chromosome 1, complete sequence
gi|1348691416|ref|NZ_CP014042.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000110356	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Pathogenic (Feb 14, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12655546, 1769645, 24296287, 25596310 Citation Link,
SCV000119321	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	no classification provided	not provided	not provided	not provided
SCV000239084	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 19, 2024)	germline	clinical testing	Citation Link,
SCV001249171	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (May 1, 2024)	germline	clinical testing	Citation Link,
SCV001930971	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001959739	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002047297	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Dec 31, 2020)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 32860008, 30389586, 1769645, 23500595, 23348723, 26467025
SCV004226633	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 30, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12655546, 1769645, 23500595, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	14	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	46	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Intra-familiar discordant PKU phenotype explained by mutation analysis in three pedigrees.

Trunzo R, Santacroce R, D'Andrea G, Longo V, De Girolamo G, Dimatteo C, Leccese A, Lillo V, Papadia F, Margaglione M.

Clin Biochem. 2014 Feb;47(3):233-5. doi: 10.1016/j.clinbiochem.2013.11.015. Epub 2013 Dec 1.

PubMed [citation]

PMID:: 24296287

Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria.

Danecka MK, Woidy M, Zschocke J, Feillet F, Muntau AC, Gersting SW.

J Med Genet. 2015 Mar;52(3):175-85. doi: 10.1136/jmedgenet-2014-102621. Epub 2015 Jan 16.

PubMed [citation]

PMID:: 25596310

See all PubMed Citations (10)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000110356.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	44	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	germline	unknown	not provided	not provided	not provided		44	not provided	not provided	not provided

From DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE, SCV000119321.1

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

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

From GeneDx, SCV000239084.11

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

Description

Associated with both a classical and a moderate PKU phenotype in patients who harbored a second variant in PAH (PMID: 12655546, 23500595); Activates a cryptic splice site in intron 10 and is expected to cause abnormal gene splicing (PMID: 1769645); Functional analysis revealed that c.1066-11 G>A is associated with 5% residual enzyme activity compared to wild type (PMID: 25596310); This variant is associated with the following publications: (PMID: 30747360, 28956315, 21147011, 19292873, 34828281, 25087612, 24296287, 22975760, 23348723, 23559577, 12655546, 1769645, 23500595, 26351554, 27469133, 26655635, 27922243, 24941924, 27121329, 28676969, 29499199, 31355225, 32533790, 31589614, 32905092, 33101986, 8188310, 34426522, 8445616, 7901929, 32778825, 29288420, 33375644, 34216551, 35405047, 37644014, 37421234, 36046396, 36646061, 37189584, 36537053, 17935162, 33465300, 32552793, 37924808, 25596310)

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

From CeGaT Center for Human Genetics Tuebingen, SCV001249171.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	14	not provided	not provided	clinical testing	not provided

Description

PAH: PM3:Very Strong, PM2, PP4:Moderate, PS3:Moderate, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		14	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001930971.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001959739.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002047297.2

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

Description

This variant is located 11 base pairs upstream of a canonical splice-acceptor site and interferes with normal PAH mRNA splicing. It has been reported to alter the splicing of exon 11 and cause the insertion of three amino acids that result in the protein having little to no residual activity (PMID: 1769645 (1991), BIOPKU (http://www.biopku.org/)). The variant is common especially in the Middle East and has been identified in families affected with classic PKU in the published literature (PMID: 23500595 (2013), 30389586 (2019), Gundorova et al. 2019 https://doi.org/10.1134/S1022795419080064). Therefore, the variant is classified as pathogenic.

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV004226633.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (4)

Description

PP3, PP4_moderate, PM2, PM3_strong, PS3

#	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		2	not provided	not provided	not provided

Last Updated: Nov 3, 2024

Relating variation to medicine