rs62516147
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4PVS1_StrongPM3_SupportingPM2
This summary comes from the ClinGen Evidence Repository: This c.1065+1G>T variant in PAH was reported in 1 patient with moderate PKU (PMID:18299955) detected with the pathogenic variant p.Leu48Ser. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. This variant in the +1 splice donor site results in exon skipping. The variant does not disrupt the reading frame, but the altered region is critical to protein function. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_strong, PM2, PP4, PM3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA312806/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.1065+1G>T | splice_donor_variant | ENST00000553106.6 | |||
PAH | NM_001354304.2 | c.1065+1G>T | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.1065+1G>T | splice_donor_variant | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1448756Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 721742
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 06, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 23, 2023 | Disruption of this splice site has been observed in individual(s) with hyperphenylalaninemia (PMID: 18299955). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 203872). This variant is also known as IVS10+1G>T. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 10 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Oct 19, 2020 | This c.1065+1G>T variant in PAH was reported in 1 patient with moderate PKU (PMID: 18299955) detected with the pathogenic variant p.Leu48Ser. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. This variant in the +1 splice donor site results in exon skipping. The variant does not disrupt the reading frame, but the altered region is critical to protein function. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_strong, PM2, PP4, PM3_supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 01, 2022 | Variant summary: PAH c.1065+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251134 control chromosomes (gnomAD). c.1065+1G>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria and Hyperphenylalaninemia) (Bercovich_2008, Li_2015, Li_2018, Wang_2018, Hillert_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed this variant since 2014: one classified the variant as likely pathogenic and the other as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000203872). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at