ClinVar Miner

Submissions for variant NM_006493.4(CLN5):c.1026_1027AT[1] (p.Thr342_Tyr343insTer) (rs386833969)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484812 SCV000568354 pathogenic not provided 2018-03-07 criteria provided, single submitter clinical testing The c.1175_1176delAT pathogenic variant in the CLN5 gene has been reported multiple times previously in association with vLINCL and is considered to be a Finnish founder mutation (Savukoski et al., 1998). Functional studies suggest that the c.1175_1176delAT variant results in an unstable protein which is unable to enter the lysosome (Schmiedt et al., 2010; Moharir et al., 2013). The deletion causes a frameshift starting with codon Tyrosine 392 and changes this amino acid to a premature Stop codon, denoted p.Tyr392Ter. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1175_1176delAT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000684967 SCV000812432 pathogenic Neuronal ceroid lipofuscinosis 2019-06-25 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CLN5 gene (p.Tyr392*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 16 amino acids of the CLN5 protein. This variant is present in population databases (rs762340626, ExAC 0.09%). This variant has been reported as homozygous in many Finnish individuals affected with Finnish variant late infantile neuronal ceroid lipofuscinosis (PMID: 9662406) and it has been observed on the opposite chromosome (in trans) from another pathogenic variant in an individual affected with a CLN5-related condition (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease.. ClinVar contains an entry for this variant (Variation ID: 2564). Experimental studies have shown that this missense change results in an unstable protein that is unable to enter the lysosomes and is been shown to be retained both in the endoplasmic reticulum and/or the Golgi (PMID: 20052765, 11971870, 24058541, 24038957). However, some studies also suggest that the CLN5 protein with this variant is targeted to the lysosome (PMID: 12134079) and has similar stability, protein maturation and glycosylation to the wild type protein (PMID: 12134079, 24038957). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000002673 SCV001164579 pathogenic Neuronal ceroid lipofuscinosis 5 2018-12-03 criteria provided, single submitter research The homozygous p.Tyr392Ter variant in CLN5 was identified by our study in two siblings with Neuronal Ceroid Lipofuscinosis. This variant has been identified in 0.08321% (21/25238) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762340626). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is seen in a greater frequency in 18 affected Finnish individuals than in the general population (PMID: 9662406). The variant is believed to be a Finnish founder variant. In vitro functional studies provide some evidence that the p.Tyr392Ter variant may impact protein function by removing a N-glycosylation site and localization to the endoplasmic reticulum instead of the lysosomes (PMID: 24058541, 20052765). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 392. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the CLN5 gene is an established disease mechanism in autosomal recessive Neuronal Ceroid Lipofuscinosis. In summary, the p.Tyr392Ter variant is pathogenic. ACMG/AMP Criteria applied: PM2, PS4, PS3, PVS1_Moderate (Richards 2015).
Myriad Women's Health, Inc. RCV000002673 SCV001194178 pathogenic Neuronal ceroid lipofuscinosis 5 2019-12-19 criteria provided, single submitter clinical testing NM_006493.2(CLN5):c.1175_1176delAT(Y392*) is classified as pathogenic in the context of CLN5-related neuronal ceroid lipofuscinosis. Sources cited for classification include the following: PMID 9662406, 10953198, 12134079, 20052765, 24038957 and 12134079. Classification of NM_006493.2(CLN5):c.1175_1176delAT(Y392*) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000002673 SCV000022831 pathogenic Neuronal ceroid lipofuscinosis 5 1998-07-01 no assertion criteria provided literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000002673 SCV000082353 pathogenic Neuronal ceroid lipofuscinosis 5 no assertion criteria provided not provided Converted during submission to Pathogenic.
GeneReviews RCV000002673 SCV000086947 pathologic Neuronal ceroid lipofuscinosis 5 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.

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