Total submissions: 35
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000000638 | SCV000852137 | pathogenic | Phenylketonuria | 2024-12-30 | reviewed by expert panel | curation | The c.1066-11G>A variant in PAH occurs within intron 10. It is predicted to impact splicing of biologically-relevant-exon 11/13. This prediction is confirmed by RT-PCR analysis which showed an in-frame insertion of Gly, Leu, Gln between exon 10 and 11 (PMID: 1769645). Nonsense mediated decay does not occur, but the resulting protein has no enzymatic activity (altered region is critical to protein function, PVS1_strong). At least one patient with this variant displayed blood Phe > 30 mg/dl, which is highly specific for PAH deficiency (PMID: 8990013). BH4 deficiency was ruled out in 1 study (PMID: 23500595). This variant has been detected in at least 23 individuals with PAH deficiency. Of those individuals, 15 were compound heterozygous for the variant and a pathogenic variant [p.R252W, p.R243X, p.R261Q (4 patients), p.R270K, p.I65T (2 patients); 5.5 points] (PMID: 23500595; PMID: 8990013) (PM3_Very strong). The population allele frequency in gnomAD v4 is 0.0003248, which is higher than the PAH VCEP cutoff for PM2 (<0.0002). In summary, this variant meets criteria to be classified as pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1_strong, PP4_Moderate, PM3_very-strong. (VCEP specifications version 2; 12/06/24) |
| Dasa | RCV000078500 | SCV007599560 | pathogenic | not provided | 2025-06-09 | criteria provided, single submitter | clinical testing | NM_000277.3(PAH):c.1066-11G>A affects a canonical splice site and is predicted to disrupt normal RNA splicing, leading to loss of normal protein function. Loss-of-function is an established mechanism of disease for this gene. This variant has been observed in affected individuals with related phenotype in a genotype context consistent with recessive disease (PMID: 38520741; PMID: 37421234; PMID: 29560316; PMID: 23500595; PMID: 8990013). Functional evidence supports a deleterious effect on the gene or gene product (PMID: 38520741; PMID: 37421234; PMID: 29560316; PMID: 23500595; PMID: 8990013). This variant has been recurrently observed in individuals with related phenotype (PMID: 38520741; PMID: 37421234; PMID: 29560316; PMID: 23500595; PMID: 8990013). Multiple computational predictions support a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic. |
| Hadassah Hebrew University Medical Center | RCV000000638 | SCV007596386 | pathogenic | Phenylketonuria | criteria provided, single submitter | research | ||
| Department of Human Genetics, |
RCV000000638 | SCV007540844 | pathogenic | Phenylketonuria | 2021-12-29 | criteria provided, single submitter | clinical testing | |
| OLLIN Analises Genomicas, |
RCV000000638 | SCV007520935 | pathogenic | Phenylketonuria | 2026-02-13 | criteria provided, single submitter | clinical testing | PVS1_S, PM3_VS, PP4_M |
| Dubai Health Genomic Medicine Center, |
RCV004798709 | SCV005420351 | pathogenic | Hyperphenylalaninemia | 2024-10-04 | criteria provided, single submitter | research | PP4_Moderate, PS3, PM3_Strong |
| Juno Genomics, |
RCV000000638 | SCV005418321 | pathogenic | Phenylketonuria | criteria provided, single submitter | clinical testing | For recessive disorders, detected in trans with a pathogenic variant.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology. | |
| Genomic Research Center, |
RCV000000638 | SCV005042983 | pathogenic | Phenylketonuria | 2024-05-06 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000000638 | SCV004848681 | pathogenic | Phenylketonuria | 2022-06-30 | criteria provided, single submitter | clinical testing | The c.1066-11G>A variant in PAH has been reported in >20 individuals with Phenylketonuria in the homozygous or compound heterozygous state and segregated with disease in multiple affected individuals (Desviat 1997 PMID: 8990013, Georgiou 2012 PMID: 22330942, Couce 2013 PMID: 23500595, Trunzo 2014 PMID: 24296287, Danecka 2015 PMID: 25596310). It has also been identified in 0.05% (38/68028) of European chromosomes by gnomAD v. 3 (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on Oct 01, 2018 by the ClinGen-approved PAH Variant Curation expert panel (Variation ID 607). Functional studies have shown that this variant activates a cryptic splice site and leads to an in-frame insertion of 3 amino acids to the transcript (Dworniczak 1991 PMID: 1769645). Additional in vitro functional studies have shown that this variant has no or little enzyme activity (Pey 2003 PMID: 12655546) and homozygotes had enzyme activity of 5% or less (Danecka 2015 PMID: 25596310). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylketonuria. ACMG/AMP Criteria applied: PM3_VS, PS3, PP1_Strong. |
| Genomic Medicine Center of Excellence, |
RCV000000638 | SCV004804989 | pathogenic | Phenylketonuria | 2024-03-17 | criteria provided, single submitter | research | |
| Mayo Clinic Laboratories, |
RCV000078500 | SCV004226633 | pathogenic | not provided | 2025-09-03 | criteria provided, single submitter | clinical testing | PP3, PP4_moderate, PM2_supporting, PM3_strong, PS3 |
| Baylor Genetics | RCV000000638 | SCV004201314 | pathogenic | Phenylketonuria | 2024-03-30 | criteria provided, single submitter | clinical testing | |
| Cellular and Molecular Medicine Research Institute, |
RCV000000638 | SCV004035235 | pathogenic | Phenylketonuria | 2023-09-19 | criteria provided, single submitter | clinical testing | pathogenic |
| Revvity Omics, |
RCV000000638 | SCV003826551 | pathogenic | Phenylketonuria | 2024-02-06 | criteria provided, single submitter | clinical testing | |
| Laboratorio de Genetica e Diagnostico Molecular, |
RCV000000638 | SCV003807550 | pathogenic | Phenylketonuria | 2022-03-08 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PS3 supporting, PM3 very strong, PP1 supporting, PP3 supporting, PP4 |
| Ambry Genetics | RCV002512611 | SCV003682432 | pathogenic | Inborn genetic diseases | 2022-05-09 | criteria provided, single submitter | clinical testing | The c.1066-11G>A intronic alteration consists of a G to A substitution 11 nucleotides before coding exon 11 in the PAH gene. Based on data from gnomAD, the A allele has an overall frequency of 0.02% (70/282062) total alleles studied. The highest observed frequency was 0.07% (5/7202) of Other alleles. This alteration has been detected in the homozygous state, and in trans with other PAH pathogenic mutations, in multiple individuals with phenylalanine hydroxylase deficiency (Tresbach, 2020; Carducci, 2020; Alsubaie, 2020; Couce, 2013; Trunzo, 2014). This nucleotide position is not well conserved in available vertebrate species. Functional assays confirm aberrant splicing that results in a 9nt in-frame insertion with a predicted protein effect of p.(Gln355_Tyr356insGlyLeuGln) (Dworniczak, 1991). Furthermore, PAH enzyme activity assays show low to absent enzyme activity in vitro and in a patient liver biopsy (Danecka, 2015; Pey, 2003; Dworniczak, 1991). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV000000638 | SCV002568298 | pathogenic | Phenylketonuria | 2022-04-21 | criteria provided, single submitter | clinical testing | PVS1, PS3, PP3 |
| Natera, |
RCV000000638 | SCV002088635 | pathogenic | Phenylketonuria | 2025-07-20 | criteria provided, single submitter | clinical testing | The c.1066-11G>A variant in PAH is an intronic variant located outside the canonical splice sites. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 26351554). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Pathogenic. |
| 3billion | RCV000000638 | SCV002058573 | pathogenic | Phenylketonuria | 2022-01-03 | criteria provided, single submitter | clinical testing | Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (, PS3_S). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000000607). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000248, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000078500 | SCV002047297 | pathogenic | not provided | 2025-04-17 | criteria provided, single submitter | clinical testing | The PAH c.1066-11G>A variant disrupts a canonical splice-acceptor site and interferes with normal PAH mRNA splicing. This variant has been reported in the published literature in as homozygous or compound heterozygous along with another PAH variant in individuals with phenylketonuria (PKU) (PMID: 37924808 (2023), 37421234 (2023), 23500595 (2013), 30389586 (2019), 8990013 (1997), 1769645 (1991), Gundorova et al. Russ J Genet 2019 55(8):102). This variant has been reported to alter the splicing of exon 11 and cause the insertion of three amino acids that results in the protein having low to absent residual enzyme activity (PMID: 1769645 (1991), 37421234 (2023), BIOPKU (http://www.biopku.org/)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper PAH mRNA splicing. Based on the available information, this variant is classified as pathogenic. |
| Institute of Human Genetics, |
RCV000000638 | SCV001440257 | pathogenic | Phenylketonuria | 2019-01-01 | criteria provided, single submitter | clinical testing | |
| CENTOGENE Gmb |
RCV000000638 | SCV001426525 | pathogenic | Phenylketonuria | criteria provided, single submitter | clinical testing | ||
| Ce |
RCV000078500 | SCV001249171 | pathogenic | not provided | 2025-12-01 | criteria provided, single submitter | clinical testing | PAH: PM3:Very Strong, PS3, PM2, PP4:Moderate, PP3 |
| Myriad Genetics, |
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.‚Äã |
| Women's Health and 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. |
| Labcorp Genetics |
RCV000000638 | SCV000629170 | pathogenic | Phenylketonuria | 2026-01-27 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 10 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of three amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs5030855, gnomAD 0.04%). This variant has been observed in individuals with phenylketonuria (PKU) (PMID: 1601425, 8990013, 22330942, 23430547, 23500595, 24296287, 25596310). It is commonly reported in individuals of European ancestry (PMID: 1601425, 8990013, 22330942, 23430547, 23500595, 24296287, 25596310). This variant is also known as p.Gln355_Tyr356insGlyLeuGln. ClinVar contains an entry for this variant (Variation ID: 607). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PAH function (PMID: 1769645, 12655546, 25596310). Studies have shown that this variant results in the activation of a cryptic splice site in intron 10 (PMID: 1769645). For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV000000638 | SCV000611228 | pathogenic | Phenylketonuria | 2022-02-17 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000078500 | SCV000239084 | pathogenic | not provided | 2025-11-03 | criteria provided, single submitter | clinical testing | Associated with both a classical and a moderate PKU phenotype in patients who harbored a second variant in PAH (PMID: 12655546, 23500595); Functional analysis revealed that c.1066-11 G>A is associated with 5% residual enzyme activity compared to wild type (PMID: 25596310); In silico analysis supports a deleterious effect on splicing; 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, 20217238, 39243181, 25596310, 39039323) |
| Eurofins Ntd Llc |
RCV000078500 | SCV000110356 | pathogenic | not provided | 2018-02-14 | criteria provided, single submitter | clinical testing | |
| Clinical Laboratory Sciences Program |
RCV000000638 | SCV003927829 | pathogenic | Phenylketonuria | 2023-04-01 | no assertion criteria provided | clinical testing | |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000078500 | SCV001959739 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Genome Diagnostics Laboratory, |
RCV000078500 | SCV001930971 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Gene |
RCV000000638 | SCV000324890 | not provided | Phenylketonuria | no classification provided | literature only | ||
| De |
RCV000078500 | SCV000119321 | not provided | not provided | no classification provided | not provided | ||
| OMIM | RCV000000638 | SCV000020788 | pathogenic | Phenylketonuria | 2007-08-15 | no assertion criteria provided | literature only |