rs62508582
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000277.3(PAH):c.1031G>T(p.Gly344Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G344D) 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 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.1031G>T | p.Gly344Val | missense_variant | 10/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.1031G>T | p.Gly344Val | missense_variant | 11/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.1031G>T | p.Gly344Val | missense_variant | 10/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Uncertain:2
Uncertain significance, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Jun 11, 2021 | The c.1031G>T (p.Gly344Val) variant in PAH has been reported in 2 siblings with classic PKU, detected with pathogenic variant p.R243Q. (PMID: 10679941). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. Other missense changes at the same amino acid residue have been seen before (p.Gly344Asp, p.Gly344Ser and p.Gly344Arg are likely pathogenic by PAH VCEP). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP3, PP4. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 24, 2018 | - - |
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