rs199475663
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.464G>C(p.Arg155Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,376 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. R155C) has been classified as Likely pathogenic.
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.464G>C | p.Arg155Pro | missense_variant | 5/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.807+1414C>G | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.464G>C | p.Arg155Pro | missense_variant | 6/14 | ||
PAH | XM_017019370.2 | c.464G>C | p.Arg155Pro | missense_variant | 5/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.464G>C | p.Arg155Pro | missense_variant | 5/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000549111.5 | n.560G>C | non_coding_transcript_exon_variant | 5/6 | 1 | ||||
PAH | ENST00000307000.7 | c.449G>C | p.Arg150Pro | missense_variant | 6/14 | 5 | |||
PAH | ENST00000551988.5 | n.530+10821G>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461376Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727016
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 20, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2022 | This variant disrupts the p.Arg155 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23514811). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 102687). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 10679941, 26666653). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 155 of the PAH protein (p.Arg155Pro). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 10, 2018 | PAH-specific ACMG/AMP criteria applied: PM2: absent from ExAC, gnomAD, 1000G, ESP. PAGE MAF=0.00066; PP3: Deleterious effect predicted in SIFT, Polyphen-2, MutationTaster. REVEL=0.967; PP4_Moderate: Detected in a patient with classic PKU. Cofactor deficiency excluded. (PMID:10679941); PM3: Detected in trans with R408W (P) (PMID:10679941). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3). - |
not provided Uncertain:1Other:1
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 29, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at