NM_000277.3(PAH):c.441+1G>A AND Phenylketonuria

Clinical significance:Pathogenic (Last evaluated: Dec 22, 2018)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000169579.9

Allele description [Variation Report for NM_000277.3(PAH):c.441+1G>A]

NM_000277.3(PAH):c.441+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.441+1G>A
HGVS:
  • NC_000012.12:g.102877461C>T
  • NG_008690.2:g.85950G>A
  • NM_000277.3:c.441+1G>AMANE SELECT
  • NM_001354304.2:c.441+1G>A
  • NC_000012.11:g.103271239C>T
  • NM_000277.1:c.441+1G>A
Links:
dbSNP: rs62517166
NCBI 1000 Genomes Browser:
rs62517166
Molecular consequence:
  • NM_000277.3:c.441+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354304.2:c.441+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000221082Counsylcriteria provided, single submitter
Likely pathogenic
(Jan 26, 2015)
unknownliterature only

PubMed (11)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000696448Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jul 18, 2016)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000754085Invitaecriteria provided, single submitter
Pathogenic
(Sep 8, 2020)
germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV001455108Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

SCV001572866ClinGen PAH Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(Dec 22, 2018)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Prevalence of tetrahydrobiopterine (BH4)-responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients.

Sterl E, Paul K, Paschke E, Zschocke J, Brunner-Krainz M, Windisch E, Konstantopoulou V, Möslinger D, Karall D, Scholl-Bürgi S, Sperl W, Lagler F, Plecko B.

J Inherit Metab Dis. 2013 Jan;36(1):7-13. doi: 10.1007/s10545-012-9485-y. Epub 2012 Apr 25.

PubMed [citation]
PMID:
22526846

Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response?

Sarkissian CN, Gamez A, Scott P, Dauvillier J, Dorenbaum A, Scriver CR, Stevens RC.

JIMD Rep. 2012;5:59-70. doi: 10.1007/8904_2011_96. Epub 2011 Dec 6.

PubMed [citation]
PMID:
23430918
PMCID:
PMC3509924
See all PubMed Citations (20)

Details of each submission

From Counsyl, SCV000221082.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (11)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696448.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: The PAH c.441+1G>A variant is located at a conserved intronic position, known to affect splicing, with 5/5 splice prediction tools predicting a significant effect on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121412, which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. Multiple publications cite the variant in affected individuals, along with multiple reputable databases/clinical laboratories classify the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000754085.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

This sequence change affects a donor splice site in intron 4 of the PAH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs62517166, ExAC 0.001%). This variant has been reported in combination with other PAH variants in several individuals affected with hyperphenylalaninemia and phenylketonuria (PMID: 7726156, 8535445, 16256386, 17096675, 20187763, 22112818, 24350308). This variant is also known as IVS4+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 102671). 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). A different variant affecting this nucleotide (c.441+1G>C) has been determined to be pathogenic (PMID: 24048906). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Experimental studies have shown that this intronic change causes an aberrant RNA splicing (PMID: 8535445). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV001455108.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen PAH Variant Curation Expert Panel, SCV001572866.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (4)

Description

The c.441+1G>A variant in PAH is a canonical splice variant in +1 splice site (exon 3/4 junction) in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (PVS1; see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria). In addition, the variant has been previously shown by RT-PCR analysis to alter RNA splicing (PS3_Supporting; PMID: 8535445). It is ultra-rare (highest observed population frequency 0.00001, with zero homozygotes, in gnomAD Non-Finnish European subpopulation), well under the PAH-specific frequency cutoff of 0.0002 (PM2). It has been found in multiple probands with classic PKU (e.g., PMID: 7726156, 8535445, 16256386, 17096675, 20187763, 22112818, 24350308, 23430918, 23764561, 8535445), although BH4 deficiency does not appear to have been formally excluded (PP4), including in trans with the Clinvar-Pathogenic R408W allele (PMID: 22112818) (PM3).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 6, 2021

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