ClinVar Genomic variation as it relates to human health

This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Rolandic epilepsy, mental retardation, and speech dyspraxia, X-linked, in X-linked Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:24995671) (PMID:23871722). PS3-Supporting => PS3 downgraded in strength to Supporting (PMID:16497722).

p.Asn327Ser (AAC>AGC): c.980 A>G in exon 9 in the SRPX2 gene (NM_014467.2).The N327S variant in the SRPX2 gene has been reported previously in association with Rolandic seizures and intellectual disability (Roll et al., 2006). The N327S variant segregated with the phenotype in multiple family members and results in a gain-of-function glycosylation that likely disrupts protein folding and function. However, Piton et al. later questioned the pathogenicity of the N327S variant because of the frequency in control populations (2013). The NHLBI ESP Exome Sequencing Project reports N327S was observed in 0.16% (11/6728) alleles from individuals of European background, including 3 hemizygous males. The N327S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar 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. We interpret N327S as a variant of unknown significance, which may be related to the reported brain malformation. The variant is found in ,SRPX2 panel(s).

The SRPX2 p.N327S variant was identified in 2 of 348 proband chromosomes (frequency: 0.0057) from individuals or families with Rolandic epilepsy (RE) and atypical RE and was present in 1 of 806 control chromosomes (frequency: 0.0012) from healthy individuals (Reinthaler_2014_PMID:24995671). Reinthaler et al. (2014) suggested the p.N327S variant does not play a major role in RE. The p.N327S variant was identified in a three generation family with atypical RE, verbal dyspraxia and cognitive impairment of variable degrees (Roll_2006_PMID:16497722). However a potentially deleterious variant, p.A716T, in the GRIN2A gene was found in a subsequent study of this family that segregated in all affected individuals (Lesca_2013_PMID:23933820). All but 2 affected family members with the SRPX2 mutation also carried the GRIN2A mutation, and all patients with the GRIN2A mutation had seizures, whereas the 2 patients with only the SRPX2 mutation and not the GRIN2A mutation did not have seizures (Lesca_2013_PMID:23933820). In another study, the p.N327S variant was identified in a boy with language and intellectual difficulties (Chen_2017_PMID:28440294). The variant was identified in dbSNP (ID: rs121918363), LOVD 3.0 (classified as likely benign) and in ClinVar (classified as benign by Invitae, likely benign by Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen and as uncertain significance by EGL Genetics, Swiss Institute of Bioinformatics, GeneDx and Genetic Services Laboratory, University of Chicago). The variant was identified in control databases in 111 of 205296 chromosomes (1 homozygous; 27 hemizygous) at a frequency of 0.000541 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 104 of 92730 chromosomes (freq: 0.001122), Other in 1 of 5338 chromosomes (freq: 0.000187), African in 3 of 18978 chromosomes (freq: 0.000158), European (Finnish) in 2 of 18621 chromosomes (freq: 0.000107) and Latino in 1 of 28049 chromosomes (freq: 0.000036), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity.The p.Asn327 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. Using an in utero Srpx2 silencing approach in mouse models, the expression of the mutant p.N327S-SRPX2 protein was found to lead to impaired development of the cerebral cortex and post-natal epileptiform activity (Salmi_2013_PMID:23831613). The p.N327S mutation was also shown to lead to gain-of-glycosylation of the mutant SRPX2 protein which causes partial retentionof the altered protein within the endoplasmic reticulumin a transfected-cell model (Roll_2006_PMID:16497722). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.