12-102844370-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.1031G>A(p.Gly344Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. G344R) has been classified as Uncertain significance.
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.1031G>A | p.Gly344Asp | missense_variant | 10/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.1031G>A | p.Gly344Asp | missense_variant | 11/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.1031G>A | p.Gly344Asp | missense_variant | 10/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461474Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727068
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:2
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Jun 11, 2021 | The c.1031G>A (p.Gly344Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 26503515). This variant is absent in population databases. This variant was detected in with multiple pathogenic variants: p.Arg241Cys (PMID: 18985011); p.R252Q (PMID: 26322415); EX6-96A>G (PMID: 29316886); p.Q232* (PMID: 30050108). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 30, 2022 | - - |
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