ClinVar Miner

Submissions for variant NM_018941.4(CLN8):c.610C>T (p.Arg204Cys)

gnomAD frequency: 0.00001  dbSNP: rs104894060
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Total submissions: 9
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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 Neuronal ceroid lipofuscinosis 8 northern epilepsy variant; Neuronal ceroid lipofuscinosis 8 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000805014 SCV000944956 pathogenic Neuronal ceroid lipofuscinosis 2023-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 204 of the CLN8 protein (p.Arg204Cys). This variant is present in population databases (rs104894060, gnomAD 0.006%). This missense change has been observed in individuals with neuronal ceroid lipofuscinosis (PMID: 15024724, 25326637). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2804). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLN8 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect CLN8 function (PMID: 15160397). This variant disrupts the p.Arg204 amino acid residue in CLN8. Other variant(s) that disrupt this residue have been observed in individuals with CLN8-related conditions (PMID: 15024724, 19807737, 23374165), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
GeneDx RCV002225256 SCV002503993 pathogenic not provided 2022-04-13 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25326637, 15024724, 30293248, 15160397, 19807737, 14997939, 15074367, 21990111, 26026925, 31589614)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV002291264 SCV002583690 likely pathogenic CLN8-related disorder 2022-09-13 criteria provided, single submitter clinical testing PM2, PM3_Strong, PP1, PP3
OMIM RCV000002938 SCV000023096 pathogenic Neuronal ceroid lipofuscinosis 8 2004-01-01 no assertion criteria provided literature only
Natera, Inc. RCV000002938 SCV002083183 pathogenic Neuronal ceroid lipofuscinosis 8 2020-11-03 no assertion criteria provided clinical testing

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