Submissions for variant NM_003793.4(CTSF):c.1046-2A>C

gnomAD frequency: 0.00025  dbSNP: rs141915593

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255055	SCV000322495	uncertain significance	not provided	2024-03-22	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31345219, 31692161)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001063136	SCV001227970	likely pathogenic	Neuronal ceroid lipofuscinosis 13	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 of the CTSF gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CTSF are known to be pathogenic (PMID: 23297359, 25274848). This variant is present in population databases (rs141915593, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with CTSF-related conditions. ClinVar contains an entry for this variant (Variation ID: 265519). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV001063136	SCV002023985	likely pathogenic	Neuronal ceroid lipofuscinosis 13	2021-06-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002401968	SCV002708759	likely pathogenic	Inborn genetic diseases	2018-03-19	criteria provided, single submitter	clinical testing	The c.1046-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 9 in the CTSF gene. This nucleotide position is highly conserved in available vertebrate species. This splice prediction software predicts that this alteration will abolish the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701360	SCV005204175	likely pathogenic	Neuronal ceroid lipofuscinosis	2024-06-20	criteria provided, single submitter	clinical testing	Variant summary: CTSF c.1046-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.3e-05 in 204312 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CTSF causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (8.3e-05 vs 0.00035), allowing no conclusion about variant significance. c.1046-2A>C has been reported in the literature in at-least one individual affected with Sporadic Ataxia (Ngo_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31692161). ClinVar contains an entry for this variant (Variation ID: 265519). Based on the evidence outlined above, the variant was classified as likely pathogenic.