Submissions for variant NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer)

dbSNP: rs386833969

Total submissions: 11

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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684967	SCV000812432	pathogenic	Neuronal ceroid lipofuscinosis	2023-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr392*) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the CLN5 protein. For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CLN5 function (PMID: 11971870, 12134079, 20052765, 24038957, 24058541). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 2564). This premature translational stop signal has been observed in individual(s) with Finnish variant late infantile neuronal ceroid lipofuscinosis (PMID: 9662406). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs762340626, gnomAD 0.08%).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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 Genetics, 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.
Genome-Nilou Lab	RCV000002673	SCV001977494	pathogenic	Neuronal ceroid lipofuscinosis 5	2021-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000684967	SCV002598840	pathogenic	Neuronal ceroid lipofuscinosis	2022-09-12	criteria provided, single submitter	clinical testing	Variant summary: CLN5 c.1028_1029delAT (p.Tyr343X)(legacy name: c.1175_1176delAT, p.Tyr392X) is located in the last exon and results in a premature termination codon, which is not predicted to cause nonsense mediated decay, but is predicted to result in a truncation of the encoded protein, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 9.4e-05 in 235034 control chromosomes (gnomAD). c.1028_1029delAT has been reported in the literature as a biallelic genotype in multiple individuals of Finnish ancestry affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and has been identified as a founder mutation within this population (e.g. Savukoski_1998, Holmberg_2000). These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown that the variant results in a protein that is retained in the endoplasmic reticulum as opposed to localizing within lysosomes, suggesting it has a negative impact on protein function (e.g. Schmiedt_2010, Moharir_2013). Six submitters have provided assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000002673	SCV005058466	pathogenic	Neuronal ceroid lipofuscinosis 5	2024-03-10	criteria provided, single submitter	clinical testing
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	not provided	Neuronal ceroid lipofuscinosis 5		no assertion provided	literature only
Natera, Inc.	RCV000684967	SCV002087987	pathogenic	Neuronal ceroid lipofuscinosis	2021-04-27	no assertion criteria provided	clinical testing