ClinVar Miner

Submissions for variant NM_018941.3(CLN8):c.610C>T (p.Arg204Cys) (rs104894060)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000002938 SCV000255344 likely pathogenic Neuronal ceroid lipofuscinosis 8 2012-08-14 criteria provided, single submitter clinical testing
Counsyl RCV000002938 SCV000797801 likely pathogenic Neuronal ceroid lipofuscinosis 8 2018-02-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763180 SCV000893779 likely pathogenic Ceroid lipofuscinosis, neuronal, 8, northern epilepsy variant; Neuronal ceroid lipofuscinosis 8 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000805014 SCV000944956 pathogenic Neuronal ceroid lipofuscinosis 2018-07-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 204 of the CLN8 protein (p.Arg204Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs104894060, ExAC 0.009%). This variant has been observed to segregate with neuronal ceroid lipofuscinosis in a family (PMID: 15024724). This variant has been also been observed as homozygous in individuals affected with neuronal ceroid lipofuscinosis (PMID: 15024724, 25326637). ClinVar contains an entry for this variant (Variation ID: 2804). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Arg204 amino acid residue in CLN8 have been observed in affected individuals (PMID: 15024724, 19807737, 23374165). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000002938 SCV001338507 pathogenic Neuronal ceroid lipofuscinosis 8 2020-04-10 criteria provided, single submitter clinical testing Variant summary: CLN8 c.610C>T (p.Arg204Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 252044 control chromosomes (gnomAD and publication). c.610C>T has been reported in the literature in multiple individuals affected with late infantile neuronal ceroid lipofuscinoses (Ranta_2004, Lee_2014) and cosegregated with the disease phenotype in the families (Ranta_2004). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000002938 SCV000023096 pathogenic Neuronal ceroid lipofuscinosis 8 2004-04-01 no assertion criteria provided literature only

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