Submissions for variant NM_018941.4(CLN8):c.562_563del (p.Leu188fs)

dbSNP: rs386834132

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000050126	SCV000220700	likely pathogenic	Neuronal ceroid lipofuscinosis 8	2014-09-16	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV001385516	SCV001585397	pathogenic	Neuronal ceroid lipofuscinosis	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu188Valfs*58) in the CLN8 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 CLN8 protein. This variant is present in population databases (rs386834132, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 22220808). ClinVar contains an entry for this variant (Variation ID: 56713). This variant disrupts a region of the CLN8 protein in which other variant(s) (p.Val236Serfs*8) have been determined to be pathogenic (Invitae). 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	RCV000050126	SCV001623276	likely pathogenic	Neuronal ceroid lipofuscinosis 8	2021-05-14	criteria provided, single submitter	clinical testing	Variant summary: CLN8 c.562_563delCT (p.Leu188ValfsX58) results in a premature termination codon located in the last exon therefore it is not expected to elicit nonsense mediated decay, but is predicted to cause a truncation of the encoded protein. Truncations downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 4e-06 in 250252 control chromosomes (gnomAD). The variant, c.562_563delCT, or the equivalent protein level change (p.Leu188Valfs), has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis, CLN8-Related (Allen_2012, Lee_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050126	SCV000082536	probable-pathogenic	Neuronal ceroid lipofuscinosis 8		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.