Submissions for variant NM_006493.4(CLN5):c.286C>T (p.Arg96Ter)

gnomAD frequency: 0.00002  dbSNP: rs386833971

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000049947	SCV000221008	likely pathogenic	Neuronal ceroid lipofuscinosis 5	2015-01-06	criteria provided, single submitter	literature only
Invitae	RCV001058589	SCV001223172	pathogenic	Neuronal ceroid lipofuscinosis	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg145*) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 263 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs386833971, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21990111). ClinVar contains an entry for this variant (Variation ID: 56534). This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392*, p.Lys368Serfs*15) have been determined to be pathogenic (PMID: 9662406, 20157158, 20960652, 22532218, 25976102). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001058589	SCV001338110	pathogenic	Neuronal ceroid lipofuscinosis	2022-07-13	criteria provided, single submitter	clinical testing	Variant summary: CLN5 c.433C>T (p.Arg145X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 251424 control chromosomes. c.433C>T has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease)(example: Kousi_2012, Giannakis_2016, Dong_2020). These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence evaluating an impact of a proline substitution in the same position having a significant impact on protein function, where the authors postulate that this region may be a mutational hotspot where changes are associated with high potential for pathogenicity (Luo_2020). Three ClinVar submitters have assessed this variant after 2014: one have classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000049947	SCV001977476	pathogenic	Neuronal ceroid lipofuscinosis 5	2021-08-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000049947	SCV004214393	pathogenic	Neuronal ceroid lipofuscinosis 5	2023-04-02	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049947	SCV000082356	probable-pathogenic	Neuronal ceroid lipofuscinosis 5		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.