rs62507324
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3_StrongPP4_ModeratePM2
This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in gnomAD+ExAC (MAF=0.00006). Absent from 1000G, ESP.; PP4_Moderate: Detected in Costa Rican and 1 Spanish PKU patients, exclusion of defects in tetrahydrobiopterine metabolism. (PMID:8860005; PMID:8981952); PM3_Strong: Detected in trans with I269L and R408W, known pathogenic variants. (PMID:9521426; PMID:23430918). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229814/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 splice_donor_region, intron
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.842+3G>C | splice_donor_region_variant, intron_variant | ENST00000553106.6 | |||
PAH | NM_001354304.2 | c.842+3G>C | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.842+3G>C | splice_donor_region_variant, intron_variant | 1 | NM_000277.3 | P1 | |||
PAH | ENST00000307000.7 | c.827+3G>C | splice_donor_region_variant, intron_variant | 5 | |||||
PAH | ENST00000635477.1 | c.3+3G>C | splice_donor_region_variant, intron_variant | 5 | |||||
PAH | ENST00000549247.6 | n.601+3G>C | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251272Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135794
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461726Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727174
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:7
Likely pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 19, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 14, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 19, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 25, 2022 | Variant summary: PAH c.842+3G>C 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: Three predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. The variant allele was found at a frequency of 1.2e-05 in 251272 control chromosomes. c.842+3G>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) in the homozygous and compound heterozygous state (eg. Santos_1996, Jeannesson-Thivisol_2015, Aldamiz-Echevarria_2016, etc). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2024 | This sequence change falls in intron 7 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs62507324, gnomAD 0.006%). This variant has been observed in individual(s) with phenylketonuria or mild hyperphenylalaninemia (PMID: 8860005, 8981952, 17096675, 19292873, 23430918, 23792259, 23942198, 24368688). This variant is also known as IVS7+3G>C. ClinVar contains an entry for this variant (Variation ID: 102871). 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. - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Sep 11, 2018 | PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in gnomAD+ExAC (MAF=0.00006). Absent from 1000G, ESP.; PP4_Moderate: Detected in Costa Rican and 1 Spanish PKU patients, exclusion of defects in tetrahydrobiopterine metabolism. (PMID:8860005; PMID:8981952); PM3_Strong: Detected in trans with I269L and R408W, known pathogenic variants. (PMID:9521426; PMID:23430918). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong). - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 11, 2022 | - - |
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 09, 2019 | The best available variant frequency is uninformative. Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 20, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at