NM_000277.3(PAH):c.707-1G>A AND Phenylketonuria

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 9, 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:: RCV000797518.9

Allele description [Variation Report for NM_000277.3(PAH):c.707-1G>A]

NM_000277.3(PAH):c.707-1G>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.707-1G>A

HGVS:

NC_000012.12:g.102852951C>T
NG_008690.2:g.110460G>A
NM_000277.3:c.707-1G>AMANE SELECT
NM_001354304.2:c.707-1G>A
NC_000012.11:g.103246729C>T
NC_000012.11:g.103246729C>T
NM_000277.1:c.707-1G>A
NM_000277.3(PAH):c.707-1G>AMANE SELECT

Links:

dbSNP: rs62507269

NCBI 1000 Genomes Browser:

rs62507269

Molecular consequence:

NM_000277.3:c.707-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354304.2:c.707-1G>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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Homo sapiens chromosome 21 open reading frame 66 (C21orf66), transcript variant ...
Homo sapiens chromosome 21 open reading frame 66 (C21orf66), transcript variant 4, mRNA
gi|22035563|ref|NM_058191.2|

Nucleotide
Zea mays uncharacterized LOC100274182 (LOC100274182), mRNA
Zea mays uncharacterized LOC100274182 (LOC100274182), mRNA
gi|226505463|ref|NM_001148556.1|

Nucleotide
Tfp1p [Saccharomyces cerevisiae JAY291]
Tfp1p [Saccharomyces cerevisiae JAY291]
gi|256270281|gb|EEU05498.1||gnl|WGS |C1Q_04144

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000937078	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 10, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 1301187, 9634518, 28492532
SCV001370815	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (May 9, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 28754886, 30747360 Citation Link,
SCV005053831	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 31, 2024)	unknown	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

SCV000937078

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 10, 2018)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001370815

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Pathogenic
(May 9, 2020)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV005053831

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 31, 2024)

unknown

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, curation

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.

Eisensmith RC, Woo SL.

Hum Mutat. 1992;1(1):13-23. Review.

PubMed [citation]

PMID:: 1301187

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000937078.3

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

Description

For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in combination with another PAH variant in several individuals affected with phenylketonuria (PMID:¬†28754886,¬†26322415).¬†This variant is also known as¬†IVS6-1G>A¬†in the literature.¬†ClinVar contains an entry for this variant (Variation ID: 102793). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 6 of the PAH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

#	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 ClinGen PAH Variant Curation Expert Panel, SCV001370815.1

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

Description

The PAH variant c.707-1G>A (IVS6-1G>A) is a null variant (acceptor site) located in exon number 7 of the PAH gene. Loss of function in the PAH gene is a known mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. This variant causes exon skipping that results in the removal of more than 10% of the transcript. This variant is predicted to disrupt the reading frame, altering regions critical to protein function (63 pathogenic non-nonsense variants in skipped exons have been reported). The mRNA transcript is predicted to undergo NMD. According to TraP in silico splicing prediction, this alteration is probably damaging (TraP score 0.572). HSF (-31.55% variation) and MaxEnt (-114.25% variation) agree that this alteration of the WT acceptor site most probably affects splicing. The PAH variant c.707-1G>A (IVS6-1G>A) was identified in three alleles from Chinese patients with classical PKU. The patients had a plasma Phe level above 120 micromol/L. DHPR activity, biopterin, and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 28754886, 30747360). The PAH variant c.707-1G>A (IVS6-1G>A) was detected in two Chinese patients with classic PKU (cPKU Phe more than 1200 micromol/L). These two patients were identified with the likely pathogenic PAH variant c.1285C>A (p.Gln429Lys) (ClinVar ID: 551555) and with the pathogenic PAH variant c.526C>T (p.Arg176Ter) (ClinVar ID: 102723) Pathogenic PM3 Points: 0.75 (Supporting) (PMID: 28754886) This variant is absent in the gnomAD, ExAC , and PAGE population databases. In summary, this variant meets the criteria to be classified as pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Supporting, PP4_Moderate, PVS1.

#	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, SCV005053831.1

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

Last Updated: Sep 29, 2024

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