rs199475614
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.992T>G(p.Phe331Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. F331L) 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.992T>G | p.Phe331Cys | missense_variant | 10/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.992T>G | p.Phe331Cys | missense_variant | 11/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.992T>G | p.Phe331Cys | missense_variant | 10/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461094Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726876
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2022 | This variant disrupts the p.Phe331 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 7833954, 23764561), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 331 of the PAH protein (p.Phe331Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 8659548; Invitae). ClinVar contains an entry for this variant (Variation ID: 102926). 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. - |
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