11-88294497-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001814.6(CTSC):c.901G>A(p.Gly301Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,958 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. G301V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001814.6 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: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000359 AC: 9AN: 251042Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135696
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461808Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 727200
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74322
ClinVar
Submissions by phenotype
Papillon-Lefèvre syndrome;C1855627:Haim-Munk syndrome;C4551681:Periodontitis, aggressive 1 Pathogenic:2
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 301 of the CTSC protein (p.Gly301Ser). This variant is present in population databases (rs104894214, gnomAD 0.01%). This missense change has been observed in individuals with Papillon-Lefèvre syndrome (PMID: 10581027, 11180012). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7297). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CTSC protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
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Papillon-Lefèvre syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at