Submissions for variant NM_001814.6(CTSC):c.1141del (p.Leu381fs)

dbSNP: rs772132996

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627422	SCV000748419	pathogenic	not provided	2018-03-14	criteria provided, single submitter	clinical testing	The c.1141delC variant in the CTSC gene has been reported previously in association with Papillon-Lefevre syndrome (Lefèvre et al., 2001; Selvaraju et al., 2003). The deletion causes a frameshift starting with codon Leucine 381, changes this amino acid to a Serine residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Leu381SerfsX13. This variant is predicted to cause loss of normal protein function through protein truncation. Specifically, it is predicted that the last 83 correct residues will be lost and replaced by 12 incorrect residues. Functional studies demonstrated that the presence of the c.1141delC variant in conjunction with another pathogenic variant results in no measurable CTSC protease activity in leukocytes (Zhang et al., 2002). Additionally, the c.1141delC variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this variant is pathogenic, and this finding is consistent with a diagnosis of a CTSC-related disorder in this patient. However, this result could also be seen if the patient had one allele with the c.1141delC pathogenic variant and one allele that was partially missing or refractory to amplification.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860488	SCV002213719	pathogenic	Haim-Munk syndrome; Periodontitis, aggressive 1; Papillon-Lefèvre syndrome	2024-09-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu381Serfs*13) in the CTSC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acid(s) of the CTSC protein. This variant is present in population databases (rs772132996, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Papillon-Lef‚àö¬Ævre syndrome (PMID: 11886537, 12112662, 29410039). ClinVar contains an entry for this variant (Variation ID: 523939). This variant disrupts a region of the CTSC protein in which other variant(s) (p.Trp429*) have been determined to be pathogenic (PMID: 10593994, 28242153, 29410039). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001860488	SCV002790703	pathogenic	Haim-Munk syndrome; Periodontitis, aggressive 1; Papillon-Lefèvre syndrome	2022-02-22	criteria provided, single submitter	clinical testing