Submissions for variant NM_006493.4(CLN5):c.459G>A (p.Met153Ile)

gnomAD frequency: 0.00058  dbSNP: rs144656959

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000724910	SCV000240645	uncertain significance	not provided	2025-03-21	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in two unrelated individuals who were suspected to have a lysosomal storage disorder; a second CLN5 variant was not identified, and no additional information was provided (PMID: 24767253); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24767253)
Eurofins Ntd Llc (ga)	RCV000724910	SCV000332348	uncertain significance	not provided	2015-06-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000367115	SCV000384727	uncertain significance	Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000536823	SCV000628965	uncertain significance	Neuronal ceroid lipofuscinosis	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 202 of the CLN5 protein (p.Met202Ile). This variant is present in population databases (rs144656959, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with lysosomal storage disease (PMID: 24767253). ClinVar contains an entry for this variant (Variation ID: 205145). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLN5 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002314705	SCV000849181	uncertain significance	Inborn genetic diseases	2024-05-13	criteria provided, single submitter	clinical testing	The c.606G>A (p.M202I) alteration is located in exon 3 (coding exon 3) of the CLN5 gene. This alteration results from a G to A substitution at nucleotide position 606, causing the methionine (M) at amino acid position 202 to be replaced by an isoleucine (I). Based on data from the Genome Aggregation Database (gnomAD) database, the CLN5 c.606G>A alteration was observed in 0.05% (146/282884) of total alleles studied, with a frequency of 0.1% (126/129190) in the European (non-Finnish) subpopulation. This variant was identified in two individuals with a clinical suspicion of a lysosomal storage disease; however, no second CLN5 variants were identified (Fernández-Marmiesse, 2014). This amino acid position is not well conserved in available vertebrate species. The p.M202I alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001113463	SCV001271238	uncertain significance	Neuronal ceroid lipofuscinosis 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome-Nilou Lab	RCV001113463	SCV002027065	uncertain significance	Neuronal ceroid lipofuscinosis 5	2021-09-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000724910	SCV002541595	uncertain significance	not provided	2021-08-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001113463	SCV001460320	uncertain significance	Neuronal ceroid lipofuscinosis 5	2020-04-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000724910	SCV001809311	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724910	SCV001968933	likely benign	not provided		no assertion criteria provided	clinical testing