rs752255985
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000277.3(PAH):c.1256A>G(p.Gln419Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,916 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q419Q) has been classified as Likely benign.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.1256A>G | p.Gln419Arg | missense_variant | 12/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.1256A>G | p.Gln419Arg | missense_variant | 13/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.1256A>G | p.Gln419Arg | missense_variant | 12/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251446Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135892
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461734Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727184
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 31, 2023 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Jun 22, 2020 | The c.1256A>G (p.Gln419Arg) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 17096675, PMID: 26503515). This variant has an extremely low allele frequency (MAF=0.00016) in gnomAD. This variant was detected in trans with multiple pathogenic variants: p.S231P (PMID: 18346471); p.Ala434Asp (PMID: 25456745); c.1068C>A (p.Y356*) (PMID: 26322415); p.Arg413Pro; p.Ala403Val; p.Val399=; p.Arg243Gln (2 patients); p.Arg53His (US); EX6-96A>G (PMID: 28982351). Computational prediction tools are conflicting. PAH-specific ACMG/AMP criteria applied: PM3_ very-strong, PM2, PP4_Moderate. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 13, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 419 of the PAH protein (p.Gln419Arg). This variant is present in population databases (rs752255985, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive phenylalanine hydroxylase deficiency (PMID: 18346471, 28982351). ClinVar contains an entry for this variant (Variation ID: 552488). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 18346471, 21820508). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at