Submissions for variant NM_005045.4(RELN):c.2066G>A (p.Cys689Tyr)

dbSNP: rs2117362100

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001757546	SCV002007773	uncertain significance	not provided	2019-06-06	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783981	SCV005397271	uncertain significance	Norman-Roberts syndrome	2022-02-25	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) which results in a cysteine to tyrosine amino acid change at residue 689 in the RELN protein. This is a novel variant which has not been reported in clinical genetics databases or observed in the medical literature in individuals with RELN-related disease, to our knowledge. This variant is absent from the gnomAD control population dataset (0/~250900 alleles). The variant occurs in the first EGF-like domain in the RELN protein (Uniprot). Multiple bioinformatic tools predict that this variant is likely to be damaging, and the Cys689 residue is highly conserved in vertebrates. Functiol studies assessing the effect of this variant on protein structure or activity have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider it to be a variant of uncertain significance. ACMG Criteria: BP1, PM2, PP3