ClinVar Miner

Submissions for variant NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) (rs386833980)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049957 SCV000221061 likely pathogenic Neuronal ceroid lipofuscinosis 5 2015-01-22 criteria provided, single submitter literature only
GeneDx RCV000187071 SCV000240646 likely pathogenic not provided 2019-01-03 criteria provided, single submitter clinical testing A published W224X variant that is likely pathogenic has been identified in the CLN5 gene. The W224X nonsense variant in the CLN5 gene has been reported previously in three individuals with juvenile neuronal ceroid lipofuscinosis (NCL), who also harbored a second variant in the CLN5 gene, however phase was not established. (Xin et al., 2010; Starpoli et al., 2012). The W224X variant is predicted to cause loss of normal protein function through protein truncation. The W224X variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Integrated Genetics/Laboratory Corporation of America RCV000049957 SCV000919230 likely pathogenic Neuronal ceroid lipofuscinosis 5 2018-03-05 criteria provided, single submitter clinical testing Variant summary: CLN5 c.671G>A (p.Trp224X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant, c.671G>A, was observed with an allele frequency of 1.2e-05 in 246410 control chromosomes. This frequency is not higher than expected for a pathogenic variant in CLN5 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (1.2e-05 vs 0.0034), allowing no conclusion about variant significance. The variant, c.671G>A, has been reported in the literature in compound heterozygote individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic". Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000818212 SCV000958813 pathogenic Neuronal ceroid lipofuscinosis 2019-12-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CLN5 gene (p.Trp224*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 184 amino acids of the CLN5 protein. This variant is present in population databases (rs386833980, ExAC 0.001%). This variant has been observed in individuals affected with neuronal ceroid lipofuscinosis (NCL) (PMID: 20157158). ClinVar contains an entry for this variant (Variation ID: 56544). This variant disrupts the C-terminus of the CLN5 protein. Other variant(s) that disrupt this region (p.Tyr342*, p.Glu352*, p.Trp379*) have been observed in affected individuals (PMID: 23374165, 19201763, 26342652). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049957 SCV000082366 probable-pathogenic Neuronal ceroid lipofuscinosis 5 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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