ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1066-3C>T (rs62507344)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000000654 SCV000220862 likely pathogenic Phenylketonuria 2014-11-06 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088742 SCV000225209 pathogenic not provided 2014-11-06 criteria provided, single submitter clinical testing
Invitae RCV000000654 SCV000836557 pathogenic Phenylketonuria 2019-11-08 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs62507344, ExAC 0.02%). This variant has been observed as homozygous in individuals affected with mild hyperphenylalaninemia or in combination with other pathogenic variants in several individuals affected with mild hyperphenylalaninemia and phenylketonuria (PMID: 8098245, 17502162, 19444284, 22526846, 22698810, 23357515 , 24368688, 26666653). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 623). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change leads to the out-of-frame skipping of exon 11 (PMID: 8098245, 22698810). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000000654 SCV000914555 pathogenic Phenylketonuria 2018-12-18 criteria provided, single submitter clinical testing Across a selection of the available literature, the PAH c.1066-3C>T splice region variant has been reported in at least six studies in which it is found in a total of 15 probands including one in a homozygous state and 14 in a compound heterozygous state (Abadie et al. 1993; Dobrowolski et al. 2009; Heintz et al. 2012; Sterl et al. 2013; Ho et al. 2014; Jeannesson-Thivisol et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (Finnish) population of the Genome Aggregation Database. Liver biopsy from a compound heterozygous proband found 1.5% of normal PAH activity (Abadie et al. 1993). RT-PCR of proband derived lymphoblast cells indicated exon 11 skipping and COS-1 cells transfected with minigenes confirmed c.1066-3C>T as the cause of exon 11 skipping (Heintz et al. 2012). Based on the evidence, the c.1066-3C>T 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.
Integrated Genetics/Laboratory Corporation of America RCV000000654 SCV001362284 pathogenic Phenylketonuria 2019-05-13 criteria provided, single submitter clinical testing Variant summary: PAH c.1066-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3' acceptor site and two predict the variant weakens a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to exon 11 skipping (Heintz_2012). The variant allele was found at a frequency of 4e-05 in 250904 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4e-05 vs 0.0079), allowing no conclusion about variant significance. c.1066-3C>T has been reported in the literature in multiple individuals affected with Phenylketonuria and Hyperphenylalaninemia (Heintz_2012, Reblova_2013, Sterl_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000654 SCV000020804 pathogenic Phenylketonuria 1993-01-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088742 SCV000119325 not provided not provided no assertion provided not provided

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