rs201245932
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PM3PM2PP4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.668A>T (p.Asn223Ile) variant in PAH has been reported in 2 individuals with PKU and MHP (BH4 deficiency excluded). (PMID:30050108). This variant has extremely low frequency in gnomAD (MAF=0.0001307). This variant was detected with in trans with p.Y166* (PMID:30050108). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748885/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.668A>T | p.Asn223Ile | missense_variant | 6/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.668A>T | p.Asn223Ile | missense_variant | 7/14 | ||
PAH | XM_017019370.2 | c.668A>T | p.Asn223Ile | missense_variant | 6/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.668A>T | p.Asn223Ile | missense_variant | 6/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000549111.5 | n.764A>T | non_coding_transcript_exon_variant | 6/6 | 1 | ||||
PAH | ENST00000307000.7 | c.653A>T | p.Asn218Ile | missense_variant | 7/14 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251334Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135830
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461850Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9AN XY: 727228
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74368
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:1Uncertain:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Jun 01, 2020 | The c.668A>T (p.Asn223Ile) variant in PAH has been reported in 2 individuals with PKU and MHP (BH4 deficiency excluded). (PMID: 30050108). This variant has extremely low frequency in gnomAD (MAF=0.0001307). This variant was detected with in trans with p.Y166* (PMID: 30050108). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 15, 2018 | - - |
PAH-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 30, 2022 | The PAH c.668A>T variant is predicted to result in the amino acid substitution p.Asn223Ile. This variant has been reported in at least two individuals with phenylketonuria, one of which was compound heterozygous with a null allele (Li et al. 2015. PubMed ID: 26503515; Li at al. 2018. PubMed ID: 30050108). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-103248952-T-A). It is classified as Likely Pathogenic in ClinVar by a ClinGen expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/549912/). Taken together, we interpret this variant to be likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at