ClinVar Miner

Submissions for variant NM_001814.6(CTSC):c.872G>A (p.Cys291Tyr)

gnomAD frequency: 0.00002  dbSNP: rs748729285
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000282638 SCV000374830 uncertain significance Papillon-Lefèvre syndrome 2017-04-27 criteria provided, single submitter clinical testing The CTSC c.872G>A (p.Cys291Tyr) missense variant has been reported in one study in which it is found in one individual with Papillon-Lefevre syndrome in a compound heterozygous state with a second missense variant (Allende et al. 2000). The p.Cys291Tyr variant was also identified in a heterozygous state in the unaffected mother. The p.Cys291Tyr variant was absent from 50 controls studied and is reported at a frequency of 0.000058 in the Genome Aggregation Database. Nagy et al. (2014) report that the p.Cys291Tyr variant occurs in the heavy chain region of the protein and may affect N-terminus positioning and tetramer formation. The evidence for this variant is limited. The p.Cys291Tyr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Papillon-Lefevre syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina RCV000349536 SCV000374831 uncertain significance Haim-Munk syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001859831 SCV002129689 uncertain significance Haim-Munk syndrome; Periodontitis, aggressive 1; Papillon-Lefèvre syndrome 2024-07-31 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 291 of the CTSC protein (p.Cys291Tyr). This variant is present in population databases (rs748729285, gnomAD 0.006%). This missense change has been observed in individuals with CTSC-related conditions (PMID: 11180601, 36740595). ClinVar contains an entry for this variant (Variation ID: 306423). 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%. 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.
Fulgent Genetics, Fulgent Genetics RCV001859831 SCV002783126 uncertain significance Haim-Munk syndrome; Periodontitis, aggressive 1; Papillon-Lefèvre syndrome 2021-11-23 criteria provided, single submitter clinical testing

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