Submissions for variant NM_018941.4(CLN8):c.792C>G (p.Asn264Lys)

gnomAD frequency: 0.00001  dbSNP: rs587779411

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Translational Research Program on Neuronal Ceroid Lipofuscinosis, Center for the Study of Inborn Errors of Metabolism	RCV000087102	SCV000676930	pathogenic	Neuronal ceroid lipofuscinosis 8		criteria provided, single submitter	research	This mutation was detected in heterozygous state, combined with a c.1A>G mutation.
Mendelics	RCV000988030	SCV001137579	likely pathogenic	Neuronal ceroid lipofuscinosis	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000087102	SCV002060048	uncertain significance	Neuronal ceroid lipofuscinosis 8	2021-11-17	criteria provided, single submitter	clinical testing	NM_018941.3(CLN8):c.792C>G(N264K) is a missense variant classified as a variant of uncertain significance in the context of CLN8-related neuronal ceroid lipofuscinosis. N264K has been observed in cases with relevant disease (PMID: 30741402, 24767253). Functional assessments of this variant are not available in the literature. N264K has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_018941.3(CLN8):c.792C>G(N264K) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Invitae	RCV000988030	SCV002162739	uncertain significance	Neuronal ceroid lipofuscinosis	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 264 of the CLN8 protein (p.Asn264Lys). This variant is present in population databases (rs587779411, gnomAD 0.007%). This missense change has been observed in individual(s) with CLN8-related conditions (PMID: 24767253, 30741402). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 100736). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
3billion	RCV000087102	SCV002521685	uncertain significance	Neuronal ceroid lipofuscinosis 8	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.74). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CLN8 related disorder (ClinVar ID: VCV000100736 / PMID: 24767253, 30741402). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.
Unidad de Diagnostico y Tratamiento de Errores Congenitos del Metabolismo. Hospital Clínico Universitário de Santiago de Compostela	RCV000087102	SCV000119959	pathogenic	Neuronal ceroid lipofuscinosis 8		no assertion criteria provided	research