Submissions for variant NM_006493.4(CLN5):c.61C>T (p.Arg21Trp)

gnomAD frequency: 0.00001  dbSNP: rs376454715

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187066	SCV000240641	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing	The R70W variant has not been publishedas a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R70W variant was notobserved with any significant frequency in approximately 6,200 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports it was observed in 2/978(0.2%) alleles from individuals of South Asian background. The R70W variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, sizeand/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis isinconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore,based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benignvariant.
Illumina Laboratory Services, Illumina	RCV000306509	SCV000384723	uncertain significance	Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000553078	SCV000628961	uncertain significance	Neuronal ceroid lipofuscinosis	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 70 of the CLN5 protein (p.Arg70Trp). This variant is present in population databases (rs376454715, gnomAD 0.06%). 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: 205141). 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: "Deleterious"; 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.
Illumina Laboratory Services, Illumina	RCV001111459	SCV001269019	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	RCV001111459	SCV002027053	uncertain significance	Neuronal ceroid lipofuscinosis 5	2021-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298245	SCV004002174	uncertain significance	Inborn genetic diseases	2023-05-23	criteria provided, single submitter	clinical testing	The c.208C>T (p.R70W) alteration is located in exon 1 (coding exon 1) of the CLN5 gene. This alteration results from a C to T substitution at nucleotide position 208, causing the arginine (R) at amino acid position 70 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001111459	SCV004235332	uncertain significance	Neuronal ceroid lipofuscinosis 5	2023-12-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000553078	SCV001460315	uncertain significance	Neuronal ceroid lipofuscinosis	2020-01-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000187066	SCV001553784	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CLN5 p.R21W variant was not identified in the literature but was identified in dbSNP (ID: rs376454715) and ClinVar (classified as uncertain significance by Invitae, GeneDx and Illumina). The variant was identified in control databases in 26 of 222450 chromosomes at a frequency of 0.0001169 (Genome Aggregation Database March 6, 2019, v2.1.1). The pR21 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.