12-102866600-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.505C>A(p.Arg169Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R169C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.505C>A | p.Arg169Ser | missense_variant | 5/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.807+1373G>T | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.505C>A | p.Arg169Ser | missense_variant | 6/14 | ||
PAH | XM_017019370.2 | c.505C>A | p.Arg169Ser | missense_variant | 5/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.505C>A | p.Arg169Ser | missense_variant | 5/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000549111.5 | n.601C>A | non_coding_transcript_exon_variant | 5/6 | 1 | ||||
PAH | ENST00000307000.7 | c.490C>A | p.Arg164Ser | missense_variant | 6/14 | 5 | |||
PAH | ENST00000551988.5 | n.530+10862C>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 169 of the PAH protein (p.Arg169Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 25449068, 26503515, 28982351, 30459323). ClinVar contains an entry for this variant (Variation ID: 932262). 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%. This variant disrupts the p.Arg169 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10234516, 18299955, 21147011, 26666653, 28982351). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | May 14, 2020 | The c.505C>A (p.Arg169Ser) variant in PAH is detected in 4 Chinese patients with Phe levels >120 umol/l (PMID 26503515, 30747360, 30050108, 28982351 ) (PP4-Moderate). The variant was detected in trans with pathogenic variants p.R241C, p.R413P, R408Q, p.R243Q (PMID: 30050108, 28982351). The validation tests on parents were performed using Sanger sequencing (PM3-Very Strong). This variant is absent from controls in gnomAD, PAGE, 100 Genomes or ESP (PM2). This variant is predicted to be damaging in SIFT, PolyPhen2, and MutationTaster. REVEL score = 0.805 (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4-Moderate, PM3-Very Strong, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 02, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at