ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1066-11G>A (rs5030855)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000638 SCV000852137 pathogenic Phenylketonuria 2018-10-01 reviewed by expert panel curation The c.1066-11G>A variant in PAH has been reported in > 76 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID: 23500595; PMID: 8990013). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with multiple known pathogenic variants: p.R243Q, p.R243X, p.R261Q, p.R270K, p.I65T. (PM3_Strong; PMID: 23500595; PMID: 8990013). Computational prediction tools and conservation analysis suggest that the c.1066-11G>A variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Strong
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078500 SCV000110356 pathogenic not provided 2018-02-14 criteria provided, single submitter clinical testing
GeneDx RCV000078500 SCV000239084 pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing The c.1066-11 G>A variant has been associated with both a classical and a moderate PKU phenotype (Pey et al., 2003; Couce et al., 2013). Functional analysis revealed that c.1066-11 G>A is associated with 5% residual enzyme activity compared to wild type (Danecka et al., 2015). The c.1066-11 G>A variant activates a cryptic splice site in intron 10 and causes abnormal gene splicing (Dworniczak et al., 1991). The responsiveness of the c.1066-11 G>A variant to BH4 therapy is not clear (Zurfluh et al., 2008; Aldámiz-Echevarría et al., 2016). In summary, we interpret c.1066-11 G>A as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000000638 SCV000611228 pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000000638 SCV000629170 pathogenic Phenylketonuria 2019-12-30 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the PAH mRNA. It does not directly change the encoded amino acid sequence of the PAH protein. This variant is present in population databases (rs5030855, ExAC 0.04%). This variant has been reported both as homozygous or in combination with another PAH variant in multiple individuals affected with phenylketonuria (PKU), being one of the most prevalent PKU-related variants in Europe (PMID: 25596310, 23500595, 24296287, 23430547, 8990013, 1601425, 22330942). This variant is also known as p.Gln355_Tyr356insGlyLeuGln. ClinVar contains an entry for this variant (Variation ID: 607). Experimental studies have shown that this missense change causes an aberrant splicing in the mRNA resulting in the insertion of three new amino acids (p.Gln355_Tyr356insGlyLeuGln) and producing a protein with null or very low enzymatic activity (PMID: 1769645, 12655546, 25596310). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000000638 SCV000696424 pathogenic Phenylketonuria 2017-01-03 criteria provided, single submitter clinical testing Variant summary: The PAH c.1066-11G>A variant is an intronic variant predicted to affect normal splicing by 4/5 splice prediction tools. This variant was found in 33/121034 control chromosomes at a frequency of 0.0002727, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant is a known pathogenic variant and is one of the most common pathogenic variants causing PKU. It activates a cryptic splice site and results in an in-frame insertion of 9 nucleotides between exon 10 and exon 11 of the processed mRNA. Normal amounts of liver PAH protein is present in homozygous patients, but no catalytic activity can be detected (Dworniczak_1991). This loss of enzyme activity is probably caused by conformational changes resulting from the insertion of three additional amino acids (Gly-Leu-Gln) between the normal sequences encoded by exon 10 and exon 11 (Dworniczak_1991). The patients who carried this variant in homozygous state were not responsive to BH4 challenge (Dobrowolski_2011). Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Myriad Women's Health, Inc. RCV000000638 SCV001194159 pathogenic Phenylketonuria 2019-10-18 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.1066-11G>A is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and is associated with the classic form of this disease. Sources cited for classification include the following: PMID 1769645 and 23500595. Classification of NM_000277.1(PAH):c.1066-11G>A is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078500 SCV001249171 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
OMIM RCV000000638 SCV000020788 pathogenic Phenylketonuria 2007-08-15 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078500 SCV000119321 not provided not provided no assertion provided not provided
GeneReviews RCV000000638 SCV000324890 pathogenic Phenylketonuria 2016-10-20 no assertion criteria provided literature only
Myriad Women's Health, Inc. RCV000000638 SCV000485253 pathogenic Phenylketonuria 2015-11-24 no assertion criteria provided clinical testing

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