Submissions for variant NM_018941.3(CLN8):c.779C>T (p.Pro260Leu) (rs146579299)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187129	SCV000240705	uncertain significance	not provided	2018-09-14	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CLN8 gene. The P260L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P260L variant is observed in 64/24030 (0.3%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The P260L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with neuronal ceroid lipofuscinosis (Stenson et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000187129	SCV000628996	likely benign	not provided	2019-01-25	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768188	SCV000898619	uncertain significance	Ceroid lipofuscinosis, neuronal, 8, northern epilepsy variant; Ceroid lipofuscinosis neuronal 8	2017-09-29	criteria provided, single submitter	clinical testing	CLN8 NM_018941.3 exon 3 p.Pro260Leu (c.779C>T): This variant has not been reported in the literature but is present in 64/24030 African individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs146579299). This variant is present in ClinVar (Variation ID:205196). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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