chr12-102840430-G-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_000277.3(PAH):c.1285C>A(p.Gln429Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,552 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. Q429P) 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 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.1285C>A | p.Gln429Lys | missense_variant | 12/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.1285C>A | p.Gln429Lys | missense_variant | 13/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.1285C>A | p.Gln429Lys | missense_variant | 12/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251444Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135892
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461400Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727038
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74322
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 10, 2023 | This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 429 of the PAH protein (p.Gln429Lys). This variant is present in population databases (rs764974157, gnomAD 0.002%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 26503515, 28982351, 30747360). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 551555). 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 not expected to disrupt PAH protein function. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 18, 2017 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Dec 09, 2018 | The c.1285C>A (p.Gln429Lys) variant in PAH is reported in a patient with mild PKU (Phe level 720). BH4 cofactor deficiency was excluded. It was detected with a known pathogenic variant, EX6-96A>G (VarID 590). (PMID: 26503515, 28982351) This variant has a low frequency in gnomAD and ExAC (MAF=0.00002), and absent in 1000G. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at