Submissions for variant NM_005045.4(RELN):c.1555G>T (p.Val519Phe) (rs560704715)
Illumina Clinical Services Laboratory,Illumina RCV000376559 SCV000465982 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.
GeneDx RCV000439689 SCV000535177 uncertain significance not provided 2016-12-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RELN gene. The c.1555 G>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1555 G>T variant is observed in 118/16,500 (0.7%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.1555 G>T may damage or destroy the natural acceptor site for intron 13 and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.1555 G>T variant does not alter splicing, it will result in the V519F missense change. The V519F variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent 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 benign variant.