ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.168+5G>C (rs62507288)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088848 SCV000330988 pathogenic not provided 2015-12-22 criteria provided, single submitter clinical testing
GeneDx RCV000088848 SCV000577366 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing The c.168+5 G>C splice site variant has been reported in association with phenylketonuria (PKU).Two individuals homozygous for the c.168+5 G>C variant were reported to have a classic PKUphenotype (Sterl et al., 2013; Anjema et al., 2013). It is predicted that this variant causes loss of thenatural splice donor site in intron 2; the adjacent exon is in-frame. We interpret c.168+5 G>C aspathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000350592 SCV000919912 pathogenic Phenylketonuria 2018-04-06 criteria provided, single submitter clinical testing Variant summary: PAH c.168+5G>C alters a non-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: Three predict the variant weakens a 5' donor site. One predicts the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-05 in 121372 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4.1e-05 vs 0.0079), allowing no conclusion about variant significance. c.168+5G>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), including numerous homozygous patients. These data indicate that the variant is very likely to be associated with disease. In addition, two overlapping variants (c.168+5G>T and c.168+5G>A) have been reported in patients, suggesting any change to this nucleotide may result in disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000350592 SCV000951830 pathogenic Phenylketonuria 2019-11-05 criteria provided, single submitter clinical testing This sequence change falls in intron 2 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 (rs62507288, ExAC 0.006%). This variant has been observed to be homozygous or in combination with another PAH variant in several individuals affected with hyperphenylalaninemia or phenylketonuria (PMID: 8364593, 21890392, 22330942, 22526846). ClinVar contains an entry for this variant (Variation ID: 102606). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000350592 SCV001138804 pathogenic Phenylketonuria 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000088848 SCV001250399 pathogenic not provided 2019-11-01 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088848 SCV000119443 not provided not provided no assertion provided not provided
Counsyl RCV000350592 SCV000789326 pathogenic Phenylketonuria 2017-02-01 no assertion criteria provided clinical testing

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