Submissions for variant NM_001814.6(CTSC):c.1276_1288A[5]CAGCTGGGCCGCAGTCCGGCCTGGGCGACAGAGCGAGACTCCGTCTCAAAAAAAAAAAAAAAAAAAGAAAAAAAAAAACCGCTGGGGCNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAACAGCTGGG[1] (p.Trp429_Gly430insAlaAlaValArgProGlyArgGlnSerGluThrProSerGlnLysLysLysLysLysLysLysLysLysAsnArgTrpGlyXaaXaaXaaXaaLysLysLysLysLysLysLysAsnSerTrp)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003785431	SCV004605046	uncertain significance	Haim-Munk syndrome; Periodontitis, aggressive 1; Papillon-Lefèvre syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 7 of the CTSC gene (c.1288_1289ins?), causing a frameshift at codon 430 (p.Gly430fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CTSC-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to disrupt protein function (PMID: 19763152, 20307669, 22406018). However the effect of this particular variant is unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.