Submissions for variant NM_006493.4(CLN5):c.808_823del (p.Gly270fs)

dbSNP: rs386833983

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000675522	SCV000230322	pathogenic	not provided	2014-11-08	criteria provided, single submitter	clinical testing
Invitae	RCV001390094	SCV001591712	pathogenic	Neuronal ceroid lipofuscinosis	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly319Phefs*12) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs776933221, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CLN5-related conditions. ClinVar contains an entry for this variant (Variation ID: 56547). This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392*) have been determined to be pathogenic (PMID: 9662406, 11971870, 20052765, 24038957, 24058541). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000675522	SCV002558287	likely pathogenic	not provided	2022-01-31	criteria provided, single submitter	clinical testing	Identified with a second CLN5 variant in an individual with neuronal ceroid lipofuscinoses, however, clinical and familial segregation information was not provided (Kousi M et al., 2012); Frameshift variant predicted to result in protein truncation, as the last 89 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21990111)
Baylor Genetics	RCV000049960	SCV004214384	pathogenic	Neuronal ceroid lipofuscinosis 5	2023-07-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001390094	SCV004223465	pathogenic	Neuronal ceroid lipofuscinosis	2023-11-07	criteria provided, single submitter	clinical testing	Variant summary: CLN5 c.808_823del16 (p.Gly270PhefsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. Variants downstream of this position have been classified as pathogenic by our laboratory and in ClinVar. The variant allele was found at a frequency of 4e-06 in 251264 control chromosomes (gnomAD). c.808_823del16 has been reported in the literature in at-least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example: Kousi_2012). The following publication has been ascertained in the context of this evaluation (PMID: 21990111). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049960	SCV000082369	probable-pathogenic	Neuronal ceroid lipofuscinosis 5		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000675522	SCV000801213	likely pathogenic	not provided	2017-06-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001390094	SCV002087979	pathogenic	Neuronal ceroid lipofuscinosis	2021-07-23	no assertion criteria provided	clinical testing