rs62517164
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000277.3(PAH):c.811C>T(p.His271Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,986 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H271L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.811C>T | p.His271Tyr | missense_variant | 7/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.811C>T | p.His271Tyr | missense_variant | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.811C>T | p.His271Tyr | missense_variant | 7/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000307000.7 | c.796C>T | p.His266Tyr | missense_variant | 8/14 | 5 | |||
PAH | ENST00000549247.6 | n.570C>T | non_coding_transcript_exon_variant | 1/6 | 2 | ||||
PAH | ENST00000635477.1 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251344Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135834
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461832Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727220
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2023 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 271 of the PAH protein (p.His271Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 9012412). ClinVar contains an entry for this variant (Variation ID: 102849). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. This variant disrupts the p.His271 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18299955). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 16, 2020 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Dec 10, 2018 | The c.811C>T (p.His271Tyr) variant in PAH has been reported in 2 unrelated PKU patients. BH4 deficiencies not assessed. (PMID: 9012412) A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.978. This variant has an extremely low frequency in ExAC, 1000G, ESP, and gnomAD (MAF=0.00001). . In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4. - |
not provided Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 10, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in two unrelated individuals with PKU, however a second variant not described in either patient (Tyfield et al., 1997); This variant is associated with the following publications: (PMID: 9012412, 25087612) - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Reduced phenylalanine hydroxylase level Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 08, 2021 | ACMG categories: PM1,PM2,PP3,BP1 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at