ClinVar Miner

Submissions for variant NM_018941.4(CLN8):c.209G>A (p.Arg70His)

gnomAD frequency: 0.00001  dbSNP: rs386834124
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000464589 SCV000549256 pathogenic Neuronal ceroid lipofuscinosis 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 70 of the CLN8 protein (p.Arg70His). This variant is present in population databases (rs386834124, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of CLN8-related conditions (PMID: 21990111, 31130284). ClinVar contains an entry for this variant (Variation ID: 56704). 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%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000623329 SCV000743028 likely pathogenic Inborn genetic diseases 2021-11-03 criteria provided, single submitter clinical testing The c.209G>A (p.R70H) alteration is located in exon 2 (coding exon 1) of the CLN8 gene. This alteration results from a G to A substitution at nucleotide position 209, causing the arginine (R) at amino acid position 70 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (7/251400) total alleles studied. The highest observed frequency was 0.01% (2/18394) of East Asian alleles. In a late infantile neuronal ceroid lipofuscinosis cohort, this alteration was detected as homozygous in two unrelated individuals and as compound heterozygous with a second CLN8 variant in another unrelated individual (Kousi, 2012). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics RCV000050117 SCV001163579 likely pathogenic Neuronal ceroid lipofuscinosis 8 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000464589 SCV003923134 likely pathogenic Neuronal ceroid lipofuscinosis 2023-03-09 criteria provided, single submitter clinical testing Variant summary: CLN8 c.209G>A (p.Arg70His) results in a non-conservative amino acid change located in the TRAM/LAG1/CLN8 homology domain (IPR006634) of 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 2.8e-05 in 251400 control chromosomes (gnomAD). c.209G>A has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Kousi_2011, Santorelli_2013, Monies_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. In addition, another missense variant in the same residue (R70C) has have been reported in the Human Gene Mutation Database in association with Epilepsy (PMID: 31069529) and classified as likely pathogenic in ClinVar database, supporting the functional importance of this residue of the protein. Three ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000050117 SCV004806696 likely pathogenic Neuronal ceroid lipofuscinosis 8 2024-03-26 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000050117 SCV000082527 probable-pathogenic Neuronal ceroid lipofuscinosis 8 no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Counsyl RCV000050117 SCV000800772 likely pathogenic Neuronal ceroid lipofuscinosis 8 2017-06-13 no assertion criteria provided clinical testing

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