rs199475567
Variant summary
Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3PM2PP4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.168G>T (p.Glu56Asp) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded) (PMID:21147011, 23932990, 30050108). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: R243Q (PMID:8019568); R408W and T356X (PMID:21147011); p.V399V, c.442-1G>A, p.I65T, p.R261Q (PMID:30050108). Computational prediction tools and conservation analysis do not agree on the impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229459/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.168G>T | p.Glu56Asp | missense_variant, splice_region_variant | 2/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.168G>T | p.Glu56Asp | missense_variant, splice_region_variant | 3/14 | ||
PAH | XM_017019370.2 | c.168G>T | p.Glu56Asp | missense_variant, splice_region_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.168G>T | p.Glu56Asp | missense_variant, splice_region_variant | 2/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 28
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2023 | For these reasons, this variant has been classified as Pathogenic. 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 102610). This missense change has been observed in individual(s) with phenylketonuria (PMID: 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 56 of the PAH protein (p.Glu56Asp). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Jun 29, 2020 | The c.168G>T (p.Glu56Asp) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded) (PMID: 21147011, 23932990, 30050108). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: R243Q (PMID: 8019568); R408W and T356X (PMID: 21147011); p.V399V, c.442-1G>A, p.I65T, p.R261Q (PMID: 30050108). Computational prediction tools and conservation analysis do not agree on the impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate. - |
not provided Other:1
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at