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

dbSNP: rs587780315

Total submissions: 8

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	RCV002316300	SCV000851085	pathogenic	Inborn genetic diseases	2016-06-24	criteria provided, single submitter	clinical testing	The c.672delG pathogenic mutation (also known as p.W224*), located in coding exon 3 of the CLN5 gene, results from a deletion of one nucleotide at nucleotide position 672, causing a translational frameshift with a predicted alternate stop codon. A different alteration, resulting in the same alternate stop codon, c.617G>A, was detected in two individuals with neuronal ceroid-lipofuscinoses phenotypes. These individuals each carried one additional CLN5 alteration; however, phase was not determined (Xin W, et al. Neurology 2010; 74(7):565-71). Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
GeneDx	RCV001008713	SCV001168493	pathogenic	not provided	2019-12-27	criteria provided, single submitter	clinical testing	Nonsense variant predicted to cause loss of normal protein function through protein truncation as the last 184 amino acids are lost; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20157158, 28542837, 23374165)
Invitae	RCV001036078	SCV001199426	pathogenic	Neuronal ceroid lipofuscinosis	2023-07-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392*) have been determined to be pathogenic (PMID: 9662406; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 128784). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinoses (PMID: 20157158, 23374165). This variant is present in population databases (rs778574270, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Trp224*) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 184 amino acid(s) of the CLN5 protein.
Baylor Genetics	RCV000116757	SCV001530516	pathogenic	Neuronal ceroid lipofuscinosis 5	2018-07-20	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. The p.W224* was previously reported in a patient with CLN5 [PMID 20157158, 23374165]
Genome-Nilou Lab	RCV000116757	SCV001977483	likely pathogenic	Neuronal ceroid lipofuscinosis 5	2021-08-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001036078	SCV002087971	pathogenic	Neuronal ceroid lipofuscinosis	2020-12-27	no assertion criteria provided	clinical testing