Submissions for variant NM_001814.6(CTSC):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00001  dbSNP: rs886048742

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV004021525	SCV000374850	uncertain significance	CTSC-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	The CTSC c.1A>G (p.Met1?) variant is predicted to disrupt the initiation codon, and thus potentially may interfere with protein expression. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Control data are unavailable for this variant which is reported at a frequency of 0.000013 in the European (non-Finnish) population of the Genome Aggregation Database. This is based on one allele in a region of good sequence coverage so is presumed to be rare. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact on protein expression and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for CTSC-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics	RCV002494957	SCV002775291	uncertain significance	Haim-Munk syndrome; Periodontitis, aggressive 1; Papillon-Lefèvre syndrome	2022-02-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002494957	SCV003340433	pathogenic	Haim-Munk syndrome; Periodontitis, aggressive 1; Papillon-Lefèvre syndrome	2022-05-20	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the CTSC mRNA. The next in-frame methionine is located at codon 57. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CTSC protein in which other variant(s) (p.Trp39Ser) have been determined to be pathogenic (PMID: 11180012). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 306433). Disruption of the initiator codon has been observed in individual(s) with Papillon-Lef√®vre syndrome and related disorders (PMID: 18723326).