rs62508718
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3_StrongPM2PP4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.649T>G (p.Cys217Gly) variant in PAH has been reported in 3 individuals with PAH deficiency (BH4 deficiency excluded). This variant is absent in population databases. This variant was detected with pathogenic variants: p.P281L (PMID:8807319), IVS10-11G>A, and p.V245A (PMID:27121329). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229673/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.649T>G | p.Cys217Gly | missense_variant | 6/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.649T>G | p.Cys217Gly | missense_variant | 7/14 | ||
PAH | XM_017019370.2 | c.649T>G | p.Cys217Gly | missense_variant | 6/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.649T>G | p.Cys217Gly | missense_variant | 6/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000549111.5 | n.745T>G | non_coding_transcript_exon_variant | 6/6 | 1 | ||||
PAH | ENST00000307000.7 | c.634T>G | p.Cys212Gly | missense_variant | 7/14 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Jul 06, 2020 | The c.649T>G (p.Cys217Gly) variant in PAH has been reported in 3 individuals with PAH deficiency (BH4 deficiency excluded). This variant is absent in population databases. This variant was detected with pathogenic variants: p.P281L (PMID: 8807319), IVS10-11G>A, and p.V245A (PMID: 27121329). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. - |
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