rs199475589
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.673C>G(p.Pro225Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P225L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.673C>G | p.Pro225Ala | missense_variant | 6/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.673C>G | p.Pro225Ala | missense_variant | 7/14 | ||
PAH | XM_017019370.2 | c.673C>G | p.Pro225Ala | missense_variant | 6/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.673C>G | p.Pro225Ala | missense_variant | 6/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000549111.5 | n.769C>G | non_coding_transcript_exon_variant | 6/6 | 1 | ||||
PAH | ENST00000307000.7 | c.658C>G | p.Pro220Ala | missense_variant | 7/14 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461810Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727214
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 14, 2023 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Feb 14, 2021 | The c.673C>G (p.Pro225Ala) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency excluded, PMID: 29499199). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. Another missense change at the same amino acid, p.Pro225Thr, is interpreted as pathogenic by multiple submitters in ClinVar (variation ID 102779). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PP3. - |
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