ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1315+1G>A (rs5030861)

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Total submissions: 21
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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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078510 SCV000110366 pathogenic not provided 2017-05-03 criteria provided, single submitter clinical testing
GeneDx RCV000078510 SCV000239096 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The c.1315+1 G>A splice site variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium Database. The c.1315+1 G>A variant is asevere PAH variant associated with a classic phenylketonuria (PKU) phenotype and is classified as notresponsive to tetrahydrobiopterin (BH4) therapy (Aulehla-Scholz C. and Heilbronner H., 2003;Zurfluh et al., 2008; Vela-Amieva et al., 2015). The c.1315+1 G>A variant destroys the canonicalsplice donor site in intron 12, and is expected to cause abnormal gene splicing. In summary, weinterpret c.1315+1 G>A as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000000606 SCV000611231 pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000000606 SCV000629184 pathogenic Phenylketonuria 2019-12-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 12) of the PAH gene. While this 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, ExAC 0.06%). This variant has been reported as homozygous or in combination with other PAH variants in multiple individuals affected with phenylketonuria, being a common cause of the disease in European populations (PMID: 9634518, 25596310, 26542770, 24368688, Invitae). ClinVar contains an entry for this variant (Variation ID: 576). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant causes exon 12 skipping. The resulting truncated protein is unstable and does not show any PAH activity (PMID: 3615198). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000000606 SCV000744088 pathogenic Phenylketonuria 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,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 2015-11-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 criteria provided, single submitter clinical testing
Myriad Women's Health, 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 Praxis fuer Humangenetik Tuebingen RCV000078510 SCV001247317 pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing
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 RCV001196422 SCV001367030 pathogenic Autistic disorder of childhood onset; High forehead; Developmental regression 2020-02-04 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
New York Genome Center RCV000078510 SCV001432828 pathogenic not provided 2020-01-21 criteria provided, single submitter clinical testing
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 pathogenic Phenylketonuria 2016-10-20 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000000606 SCV000733120 pathogenic Phenylketonuria no assertion criteria provided clinical testing

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