Submissions for variant NM_001814.6(CTSC):c.1201G>A (p.Glu401Lys)

gnomAD frequency: 0.00009  dbSNP: rs200627023

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801862	SCV000941660	uncertain significance	Haim-Munk syndrome; Periodontitis, aggressive 1; Papillon-Lefèvre syndrome	2022-07-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 401 of the CTSC protein (p.Glu401Lys). This variant is present in population databases (rs200627023, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with CTSC-related conditions. ClinVar contains an entry for this variant (Variation ID: 647363). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). 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.
Illumina Laboratory Services, Illumina	RCV001111678	SCV001269253	uncertain significance	Papillon-Lefèvre syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001111679	SCV001269254	uncertain significance	Haim-Munk syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000801862	SCV002496092	uncertain significance	Haim-Munk syndrome; Periodontitis, aggressive 1; Papillon-Lefèvre syndrome	2021-07-16	criteria provided, single submitter	clinical testing	CTSC NM_001814.5 exon 7 p.Glu401Lys (c.1201G>A):This variant has been reported in the literature in 1 family with Papillon-Lefevre syndrome, however this variant was not present in the affected individual in the family and a different variant was identified in the affected individual that is likely causative of disease (Lefevre 2001 PMID:11886537). This variant is present in 0.03% (5/15246) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-88294197-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:647363). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
AiLife Diagnostics, AiLife Diagnostics	RCV001529391	SCV002503397	uncertain significance	not provided	2020-07-02	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529391	SCV001742761	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529391	SCV001969966	uncertain significance	not provided		no assertion criteria provided	clinical testing