ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1315+1G>A

gnomAD frequency: 0.00040  dbSNP: rs5030861
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Total submissions: 33
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000606 SCV000852099 pathogenic Phenylketonuria 2018-08-05 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PS3: abolishes PAH activity due to protein instability (PMID:17935162; PMID:3615198); PM3: (PMID:24941924); PP4_Moderate: Reported in Galician PAH deficiency population. BH4 deficiency ruled out. (PMID:23500595); PVS1: Canonical +1 splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM3, PP4_Moderate, PVS1).
Eurofins Ntd Llc (ga) RCV000078510 SCV000110366 pathogenic not provided 2017-05-03 criteria provided, single submitter clinical testing
GeneDx RCV000078510 SCV000239096 pathogenic not provided 2020-02-25 criteria provided, single submitter clinical testing Published functional studies demonstrate c.1315+1 G>A results in deletion of exon 12 and abolishes phenylalanine hydroxylase activity due to protein instability (Marvit et al., 1987); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al., 2008; Vela-Amieva et al., 2015); This variant is associated with the following publications: (PMID: 3008810, 23559577, 3018584, 22975760, 11914042, 26666653, 8406445, 24368688, 17935162, 25525159, 21228398, 3615198, 25087612, 24941924, 12655553, 11999982, 2014036, 26542770, 23500595, 24190797, 22526846, 30963030, 31589614, 33101986, 8188310, 32853555, 1677425)
Fulgent Genetics, Fulgent Genetics RCV000000606 SCV000611231 pathogenic Phenylketonuria 2022-03-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000000606 SCV000629184 pathogenic Phenylketonuria 2024-01-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the PAH gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs5030861, gnomAD 0.08%). Disruption of this splice site has been observed in individual(s) with PAH-related conditions (PMID: 24368688, 25596310, 26542770). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 9634518, 24368688, 25596310, 26542770; Invitae). ClinVar contains an entry for this variant (Variation ID: 576). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects PAH function (PMID: 3615198, 17935162). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000606 SCV000696436 pathogenic Phenylketonuria 2016-05-06 criteria provided, single submitter clinical testing Variant summary: The c.1315+1G>A variant affects a conserved intronic nucleotide. One in-silico tool predicts damaging outcome for this variant and 5/5 splice-tools in Alamut predict that this variant abolishes a splice donor site at intron 12. This variant is found in 42/121228 control chromosomes at a frequency of 0.0003465, which does not exceed maximal expected frequency of a pathogenic allele (0.0079057). The variant has been reported in numerous affected individuals in the literature, is considered a common pathogenic variant in European populations, and has been shown to results in the complete absence of PAH activity. In addition, multiple reputable clinical labs have classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Ambry Genetics RCV000622610 SCV000742847 pathogenic Inborn genetic diseases 2021-01-05 criteria provided, single submitter clinical testing The c.1315+1G>A intronic alteration consists of a G to A substitution one nucleotide after coding exon 12 of the PAH gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the PAH c.1315+1G>A alteration was observed in 0.04% (112/282,806) of total alleles studied, with a frequency of 0.08% (105/129,170) in the European (non-Finnish) subpopulation. The c.1315+1G>A alteration has been observed in both the homozygous state and compound heterozygous state in multiple unrelated individuals (Dihella 1986; Tabor, 2014; Xiong, 2015). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000000606 SCV000744088 pathogenic Phenylketonuria 2014-10-08 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000000606 SCV000745568 pathogenic Phenylketonuria 2016-10-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078510 SCV000888344 pathogenic not provided 2024-04-02 criteria provided, single submitter clinical testing The PAH c.1315+1G>A variant disrupts a canonical splice-donor site and interferes with normal PAH mRNA splicing. This variant has been reported in homozygous or compound heterozygous states in multiple individuals with PKU (PMIDs: 9634518 (1998), 24368688 (2014), 24941924 (2015), 25596310 (2015), 26542770 (2016), 33375644 (2020), 34828281 (2021)). Experimental studies indicate that this variant results in skipping of exon 12 in mRNA derived from patient cells and it has to very low PAH activity due to protein instability (PMIDs: 3615198 (1987), 17935162 (2008)). The frequency of this variant in the general population, 0.001 (51/50816 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV000000606 SCV000914551 pathogenic Phenylketonuria 2017-04-28 criteria provided, single submitter clinical testing Across a selection of the available literature, the PAH c.1315+1G>A variant, which occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product, is noted as one of the prevalent variants in the PAH gene. This variant has been identified in a homozygous state in at least 22 individuals with phenylalanine hydroxylase deficiency, in a compound heterozygous state in 151 patients, and in a heterozygous state in two patients (Guldberg et al. 1998; Koch et al. 2002; Bell et al. 2011; Bayat et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00105 in the European American population of the Exome Sequencing Project. The c.1315+1G>A variant was shown to cause skipping of exon 11, leading to loss of protein function (Marvit et al. 1987; Heintz et al. 2013; Couce et al. 2013). Based on the evidence from the literature and the potential impact of splice donor variants, the c.1315+1G>A variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics RCV000000606 SCV001163708 pathogenic Phenylketonuria 2024-03-30 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000000606 SCV001194237 pathogenic Phenylketonuria 2019-12-20 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.1315+1G>A is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. The c.1315+1G>A variant is associated with classic PKU. Sources cited for classification include the following: PMID 22526846, 17502162, 9634518, 2014036 and 17935162. Classification of NM_000277.1(PAH):c.1315+1G>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 Center for Human Genetics Tuebingen RCV000078510 SCV001247317 pathogenic not provided 2024-05-01 criteria provided, single submitter clinical testing PAH: PM3:Very Strong, PVS1, PM2, PP4:Moderate, PS3:Moderate
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill RCV000000606 SCV001251467 pathogenic Phenylketonuria criteria provided, single submitter research The PAH c.1315+1G>A (p.?) variant is predicted to disrupt a canonical donor splice site. This variant is considered a severe PAH variant that has been observed in autosomal recessive classic phenylketonuria and is not responsive to tetrahydrobiopterin therapy. This variant has also been referred to in the literature as IVS12+1G>A (PMID: 3615198; 23500595; 12655544; 24190797; 17935162).
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000000606 SCV001367030 pathogenic Phenylketonuria 2020-02-04 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
New York Genome Center RCV004799176 SCV001432828 pathogenic Pituitary hormone deficiency, combined, 2 2020-01-21 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000000606 SCV001448977 pathogenic Phenylketonuria 2018-08-10 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000078510 SCV002009278 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000000606 SCV002016490 pathogenic Phenylketonuria 2023-12-28 criteria provided, single submitter clinical testing
3billion RCV000000606 SCV002059116 pathogenic Phenylketonuria 2022-01-03 criteria provided, single submitter clinical testing Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 3615198, 17935162, PS3_S). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000000576, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000396, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 24941924, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology RCV000000606 SCV002761837 pathogenic Phenylketonuria 2022-01-13 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003407249 SCV004106519 pathogenic PAH-related disorder 2023-10-12 criteria provided, single submitter clinical testing The PAH c.1315+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, often referred to in the literature as IVS12+1G>A, disrupts the consensus splice donor site that lies at the junction of exon 12 and intron 12 and is predicted to adversely affect normal gene splicing (Alamut Visual v2.11). This variant has been reported to be causative for phenylalanine hydroxylase deficiency (e.g., Dobrowolski et al. 2009. PubMed ID: 19444284; Couce et al. 2013. PubMed ID: 23500595; Vela-Amieva et al. 2015. PubMed ID: 24941924; Sarkissian et al. 2012. PubMed ID: 23430918). The c.1315+1G>A variant has been reported to completely abrogate phenylalanine hydroxylase enzyme activity and has been associated with classic phenylketonuria (PKU) (Zurflüh et al. 2008. PubMed ID: 17935162; Couce et al. 2013. PubMed ID: 23500595). Additionally, it has been reported to result in a PAH protein that is non-responsive to BH4 (Zurflüh et al. 2008. PubMed ID: 17935162). This variant is classified as pathogenic by multiple outside laboratories and the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/576/). Based on these observations, we interpret this variant as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000000606 SCV004847982 pathogenic Phenylketonuria 2016-02-01 criteria provided, single submitter clinical testing The c.1315+1G>A variant in PAH is a well-established variant in patients with classic PKU (Okano 1991, Zurfluh 2008). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein and in vitro functional studies provide evidence that the c.1315+1G>A variant impacts protein function (Okano 1991, Couce 2013, Heintz 2013, Zurfluh 2008, ). This variant has been identified in 0.06% (40/66664) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs5030861). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets our criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner.
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000078510 SCV005197065 pathogenic not provided 2022-05-27 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000078510 SCV005414098 pathogenic not provided 2024-01-22 criteria provided, single submitter clinical testing PP4_moderate, PM3, PS3, PVS1
OMIM RCV000000606 SCV000020756 pathogenic Phenylketonuria 1987-07-24 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078510 SCV000119418 not provided not provided no assertion provided not provided
GeneReviews RCV000000606 SCV000324892 not provided Phenylketonuria no assertion provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000000606 SCV000733120 pathogenic Phenylketonuria no assertion criteria provided clinical testing
Natera, Inc. RCV000000606 SCV001458993 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000078510 SCV001809008 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000078510 SCV001958569 pathogenic not provided no assertion criteria provided clinical testing

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