Submissions for variant NM_006493.4(CLN5):c.777_778del (p.Phe260fs)

dbSNP: rs786204644

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169429	SCV000220840	likely pathogenic	Neuronal ceroid lipofuscinosis 5	2014-10-27	criteria provided, single submitter	literature only
GeneDx	RCV000413943	SCV000491175	likely pathogenic	not provided	2022-11-07	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 99 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 22532218)
Invitae	RCV000468638	SCV000549225	pathogenic	Neuronal ceroid lipofuscinosis	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe309Serfs*12) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs769059034, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 22532218). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189038). This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392*) have been determined to be pathogenic (PMID: 9662406). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000468638	SCV000919231	likely pathogenic	Neuronal ceroid lipofuscinosis	2022-05-19	criteria provided, single submitter	clinical testing	Variant summary: CLN5 c.924_925delAT (p.Phe309SerfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.6e-05 in 251266 control chromosomes, predominantly at a frequency of 0.00026 within the Latino subpopulation in the gnomAD database. c.924_925delAT has been reported in the literature in one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002372061	SCV002687621	pathogenic	Inborn genetic diseases	2020-01-22	criteria provided, single submitter	clinical testing	The c.924_925delAT pathogenic mutation, located in coding exon 4 of the CLN5 gene, results from a deletion of two nucleotides at nucleotide positions 924 to 925, causing a translational frameshift with a predicted alternate stop codon (p.F309Sfs*12). This alteration was detected in trans with a second truncating alteration in CLN5 in an individual with neuronal ceroid lipofuscinosis (NCL) (Pérez-Poyato M S et al. Rev Neurol, 2012 May;54:544-50). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000169429	SCV002804825	pathogenic	Neuronal ceroid lipofuscinosis 5	2021-08-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169429	SCV004214371	pathogenic	Neuronal ceroid lipofuscinosis 5	2023-10-09	criteria provided, single submitter	clinical testing