rs62642908
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.770G>T(p.Gly257Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G257C) 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.770G>T | p.Gly257Val | missense_variant | 7/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.770G>T | p.Gly257Val | missense_variant | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.770G>T | p.Gly257Val | missense_variant | 7/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000307000.7 | c.755G>T | p.Gly252Val | missense_variant | 8/14 | 5 | |||
PAH | ENST00000549247.6 | n.529G>T | non_coding_transcript_exon_variant | 1/6 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461848Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727228
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 02, 2018 | Variant summary: PAH c.770G>T (p.Gly257Val) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246102 control chromosomes (in gnomAD). c.770G>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Liang 2014, Li 2015, Liu 2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Liang 2014). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Nov 14, 2020 | The c.770G>T (p.Gly257Val) 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 with multiple pathogenic variants: p.R408Q, p.Ser70del (PMID: 26322415); p.R111X (PMID: 14722928); p.Arg261Gln (PMID: 17502162); c.1068C>A (p.Y356*, PMID: 25894915); p.Arg252Trp, p.Arg243Gln, p.His107Arg, p.Leu255Ser (PMID: 28982351). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 08, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 25, 2017 | - - |
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