ClinVar Miner

Submissions for variant NM_006493.4(CLN5):c.525del (p.His174_Trp175insTer) (rs587780315)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000116757 SCV000150732 pathogenic Neuronal ceroid lipofuscinosis 5 2013-08-27 criteria provided, single submitter clinical testing
Counsyl RCV000116757 SCV000220901 likely pathogenic Neuronal ceroid lipofuscinosis 5 2014-11-20 criteria provided, single submitter literature only
Ambry Genetics RCV000720208 SCV000851085 pathogenic Seizures 2016-06-24 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV001008713 SCV001168493 likely pathogenic not provided 2019-08-12 criteria provided, single submitter clinical testing A nonsense variant that is likely pathogenic has been identified in the CLN5 gene. The c.672delG variant has been previously reported in the homozygous and heterozygous states in association with neuronal ceroid lipofuscinosis (Santorelli et al., 2013; Simonati et al., 2017). Functional studies performed on cells derived from an individual harboring c.672delG and a second CLN5 variant support premature protein truncation; however, phase of these variants was not known (Simonati et al., 2017). The c.672delG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function through protein truncation as the last 184 amino acids are lost. A different nucleotide change leading to the same protein change is reported in the Human Gene Mutation Database in individuals with vLINCL (Xin et al. 2010; Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001036078 SCV001199426 pathogenic Neuronal ceroid lipofuscinosis 2019-12-20 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 (rs778574270, ExAC 0.006%). This variant has been observed in individual(s) with neuronal ceroid lipofuscinoses (PMID: 23374165). ClinVar contains an entry for this variant (Variation ID: 128784). A different variant (c.671G>A) giving rise to the same protein effect observed here (p.Trp224*) has been determined to be pathogenic (PMID: 20157158). This suggests that this variant is also likely to be causative of disease. This variant disrupts the C-terminus of the CLN5 protein. Other variant(s) that disrupt this region (p.Tyr392*) have been determined to be pathogenic (PMID: 9662406, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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