Submissions for variant NM_005045.4(RELN):c.8863C>T (p.Arg2955Cys) (rs114501042)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000657945	SCV000231370	uncertain significance	not provided	2018-08-10	criteria provided, single submitter	clinical testing
Invitae	RCV001079326	SCV000656369	likely benign	Norman-Roberts syndrome; Epilepsy, familial temporal lobe, 7	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000657945	SCV000779715	uncertain significance	not provided	2018-05-21	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RELN gene. The R2955C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 80/18854 (0.4%) alleles from individuals of East Asian background in large population cohorts (Lek et al., 2016). The R2955C 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. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina	RCV001161856	SCV001323766	likely benign	Norman-Roberts syndrome	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.