rs41270025
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001122764.3(PPOX):c.503G>A(p.Arg168His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,970 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. R168C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001122764.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74296
ClinVar
Submissions by phenotype
Variegate porphyria Pathogenic:3
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not provided Pathogenic:3
The R168H variant in the PPOX gene has been reported previously in association with variegate porphyria (Frank et al., 1998; Whatley et al., 1999; Frank et al., 2001; Rossetti et al., 2008). The R168H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R168H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. Functional studies demonstrate R168H disrupts the hydrogen bond network, and has a 50-fold decrease in catalytic activity (Qin et al., 2011). We interpret R168H as a pathogenic variant. -
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 168 of the PPOX protein (p.Arg168His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with variegate porphyria (PMID: 9738863, 10486317, 11173967, 18570668, 19845869, 28653968). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8697). 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 PPOX protein function. Experimental studies have shown that this missense change affects PPOX function (PMID: 11929051, 21048046). -
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See cases Pathogenic:1
ACMG classification criteria: PS3, PS4, PM2, PP1, PP2, PP4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at