ClinVar Miner

Submissions for variant NM_000086.2(CLN3):c.1000C>T (p.Arg334Cys) (rs386833694)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588369 SCV000697651 likely pathogenic Neuronal ceroid lipofuscinosis 2019-03-21 criteria provided, single submitter clinical testing Variant summary: CLN3 c.1000C>T (p.Arg334Cys) 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 was absent in 275064 control chromosomes (gnomAD). c.1000C>T has been reported in the literature in individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease). These data indicate that the variant may be associated with disease. The c.1000C>T variant has been reported in the literature in several individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease), indicating that the variant may be associated with disease. Additionally, a variant affecting the same codon c.1001G>A (p.R334H) was also observed in 4 families with classical JNCL phenotype, indicating residue 334 is likely critical for normal function of the CLN3 protein. The variant is located in the third lumenal region on the predicted lumenal face of a putative amphipathic helix, and all proteins mutated in this region were defective in function observed by a functional study (Haines_2009), suggesting this region has a significant effect on the 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 likely pathogenic.
Invitae RCV000588369 SCV001232832 pathogenic Neuronal ceroid lipofuscinosis 2019-02-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 334 of the CLN3 protein (p.Arg334Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs386833694, ExAC 0.01%). This variant has been observed in individuals with neuronal ceroid lipofuscinosis (PMID: 9311735, 25976102, 17475770, 21990111). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56243). This variant has been reported to affect CLN3 protein function (PMID: 19132115, 11589014, 10924275, 17475770). This variant disrupts the p.Arg334 amino acid residue in CLN3. Other variant(s) that disrupt this residue have been observed in individuals with CLN3-related conditions (PMID: 21990111, 21499717, 23539563, 9311735, 20187884), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049655 SCV000082062 probable-pathogenic Juvenile neuronal ceroid lipofuscinosis no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Counsyl RCV000049655 SCV001132155 likely pathogenic Juvenile neuronal ceroid lipofuscinosis 2018-10-16 no assertion criteria provided clinical testing

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