Submissions for variant NM_001814.6(CTSC):c.203T>G (p.Leu68Arg)

dbSNP: rs199474831

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001041477	SCV001205098	pathogenic	Haim-Munk syndrome; Periodontitis, aggressive 1; Papillon-Lefèvre syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 68 of the CTSC protein (p.Leu68Arg). This variant is present in population databases (rs199474831, gnomAD 0.02%). This missense change has been observed in individuals with Papillon-Lef√®vre syndrome (PMID: 23311634). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 839668). 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 CTSC protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001270860	SCV001451633	likely pathogenic	CTSC-Related Disorders	2019-01-10	criteria provided, single submitter	clinical testing	The CTSC c.203T>G (p.Leu68Arg) variant is a missense variant located in the exclusion domain of the cathepsin C protein. The p.Leu68Arg variant has been reported in one study, in which it is found in nine individuals with Papillon-Lefevre syndrome (PLS), including in seven in a homozygous state and in two in a compound heterozygous state with a second missense variant (Romero-Quintana et al. 2013). In one family, three affected members presented with variable expression of PLS. One sibling showed overt palmoplantar hyperkeratosis with fissures, loss of deciduous teeth, and swelling and inflammation of the gums while her sister presented with ever mild hyperkeratosis, severe periodontitis, and recurrent bacterial skin infections. Their paternal uncle at 61 years of age had mild hyperkeratosis with loss of all teeth. The p.Leu68Arg variant was absent from 200 control alleles but is reported at a frequency of 0.000238 in the Latino population of the Genome Aggregation Database. Affected individuals showed 14.89% of the enzymatic activity as compared to controls (100%), while carrier parents and siblings showed 47.60% and 38.42% enzymatic activity, respectively (Romero-Quintana et al. 2013). Based on the collective evidence and application of the ACMG criteria, the p.Leu68Arg variant is classified as likely pathogenic for CTSC-related disorders.
Fulgent Genetics, Fulgent Genetics	RCV001041477	SCV002813253	likely pathogenic	Haim-Munk syndrome; Periodontitis, aggressive 1; Papillon-Lefèvre syndrome	2021-10-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003953437	SCV004768780	pathogenic	CTSC-related condition	2024-01-11	criteria provided, single submitter	clinical testing	The CTSC c.203T>G variant is predicted to result in the amino acid substitution p.Leu68Arg. This variant was reported in the homozygous state or compound heterozygous state in multiple individuals with Papillon Lefèvre Syndrome (Romero-Quintana et al. 2013. PubMed ID: 23311634). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.