rs199475584
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3PS3PP4_ModeratePM2
This summary comes from the ClinGen Evidence Repository: The c.1197A>T (p.Val399=) variant in PAH has been reported on 7 alleles of PKU patients (BH4 deficiency excluded). (PP4_Moderate; PMID:23271928; PMID:11214902). This variant has an extremely low allele frequency (0.000004064) in gnomAD (PM2; http://gnomAD.broadinstitute.org). This variant induces post-transcriptional skipping of exon 11 (PS3; PMID:11214902). This variant was detected in trans with R408W (Pathogenic in ClinVar) (PM3; PMID:11214902). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA229379/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.1197A>T | p.Val399= | splice_region_variant, synonymous_variant | 11/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.1197A>T | p.Val399= | splice_region_variant, synonymous_variant | 12/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.1197A>T | p.Val399= | splice_region_variant, synonymous_variant | 11/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251286Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135818
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461518Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727056
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change affects codon 399 of the PAH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PAH protein. This variant is present in population databases (rs199475584, gnomAD 0.006%). This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 24401910, 27264808). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 601). 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 11, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 13, 2021 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Jul 28, 2018 | The c.1197A>T (p.Val399=) variant in PAH has been reported on 7 alleles of PKU patients (BH4 deficiency excluded). (PP4_Moderate; PMID: 23271928; PMID: 11214902). This variant has an extremely low allele frequency (0.000004064) in gnomAD (PM2; http://gnomAD.broadinstitute.org). This variant induces post-transcriptional skipping of exon 11 (PS3; PMID: 11214902). This variant was detected in trans with R408W (Pathogenic in ClinVar) (PM3; PMID: 11214902). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 05, 2016 | Variant summary: The PAH c.1197A>T (p.Val399Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. It is located three nucleotides upstream from exon-intron boundary and is predicted to be damaging by MutationTaster. In addition, 2/5 tools predict the variant to attenuate the splice donor site while 4/5 tools predict the variant to attenuate the cryptic splice site located at upstream to this variant position. Functional study by patients RNA analysis as well as minigene assay proves that this variant is a splicing mutation causing skipping of exon 11 (Chao_2001). This variant was found in 15/121712 control chromosomes at a frequency of 0.0001232, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant is a common pathogenic variant causing classical PKH, especially in Chinese and/or Taiwanese population with consistent clinical data. The carrier rate of this variant in Han Chinese population was 3.2% in a study that enrolled 212 controls (Zhu_2010). Multiple reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 19, 2015 | - - |
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 14, 2022 | Published functional studies demonstrates this variant leads to skipping of exon 11 and decreased PAH activity (Chao et al., 2001; Liang et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23225039, 25550961, 19199246, 9949232, 7893121, 24705691, 22333022, 17557229, 20140859, 11214902, 26503515, 16825284, 23932990, 19915519, 14722928, 27173423, 20017307, 29317692, 30747360, 30275481, 27264808, 29499199, 31355225, 1997387, 23271928, 32668217, 25894915, 24401910) - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 18, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at