Submissions for variant NM_006493.4(CLN5):c.904A>G (p.Lys302Glu)

gnomAD frequency: 0.00001  dbSNP: rs1060502320

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000469030	SCV000549222	uncertain significance	Neuronal ceroid lipofuscinosis	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with glutamic acid at codon 351 of the CLN5 protein (p.Lys351Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CLN5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV000479788	SCV000570757	uncertain significance	not provided	2016-06-30	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CLN5 gene. The K351E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K351E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Genome-Nilou Lab	RCV001785619	SCV002027076	uncertain significance	Neuronal ceroid lipofuscinosis 5	2021-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002523317	SCV003570768	uncertain significance	Inborn genetic diseases	2021-08-09	criteria provided, single submitter	clinical testing	The c.1051A>G (p.K351E) alteration is located in exon 4 (coding exon 4) of the CLN5 gene. This alteration results from a A to G substitution at nucleotide position 1051, causing the lysine (K) at amino acid position 351 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Athena Diagnostics Inc	RCV000479788	SCV004229543	uncertain significance	not provided	2023-07-27	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging.
Natera, Inc.	RCV000469030	SCV002087983	uncertain significance	Neuronal ceroid lipofuscinosis	2020-07-30	no assertion criteria provided	clinical testing