ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.1001G>A (p.Arg334His) (rs386833695)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049656 SCV000220558 likely pathogenic Neuronal ceroid lipofuscinosis 3 2014-07-30 criteria provided, single submitter literature only
Invitae RCV000696638 SCV000825206 pathogenic Neuronal ceroid lipofuscinosis 2020-08-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 334 of the CLN3 protein (p.Arg334His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs386833695, ExAC 0.02%). This variant has been reported in the homozygous or compound heterozygous state in several individuals affected with juvenile neuronal ceroid lipofuscinosis (PMID: 21990111, 21499717, 23539563, 9311735, 20187884). ClinVar contains an entry for this variant (Variation ID: 56244). Experimental studies have shown that this missense change impairs protein function without affecting CLN3 abundance (PMID: 19132115, 23539563). A different missense substitution at this codon (p.Arg334Cys) has been determined to be pathogenic (PMID: 21990111, 9311735, 19132115). This suggests that the arginine residue is critical for CLN3 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049656 SCV000917249 pathogenic Neuronal ceroid lipofuscinosis 3 2018-07-24 criteria provided, single submitter clinical testing Variant summary: CLN3 c.1001G>A (p.Arg334His) 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 2.5e-05 in 275154 control chromosomes (gnomAD and publications). The variant, c.1001G>A, has been reported in the literature in individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease)(Munroe_1997; Miller_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Haines_2009, Miller_2013). The most pronounced variant effect results in 10%-<30% of normal activity (Haskell_2000). Another variant at the same codon (p.R334C) has been associated with Juvenile Neuronal Ceroid-Lipofuscinosis, suggesting the codon is critical for protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049656 SCV000082063 probable-pathogenic Neuronal ceroid lipofuscinosis 3 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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