Concern regarding classification of c.703G>A/p.Gly235Arg as a novel missense variant in KRIT1 gene

Response to: Concern regarding classification of c.703G>A/p.Gly235Arg as a novel missense variant in KRIT1 gene

“…Nevertheless, we cannot exclude that the c.703G>A still maintains some pathogenic role by affecting splicing in substitution or in combination with the predicted missense change. In fact, more extensive molecular studies could better characterize the structure of the alternative transcript identified by Battistini and Ricci (2020), in comparison with the deposited transcript NM_001350671.1 and, eventually, confirm the hypothesis. We can also assume a differential effect on splicing of the c.703G>A variant in the various tissues with a predominance in vascular tissue compared with the wild-type sequence.…”

“…We can also assume a differential effect on splicing of the c.703G>A variant in the various tissues with a predominance in vascular tissue compared with the wild-type sequence. Finally, as the alternative transcript presumably generated by the c.703G>A variant corresponds to NM_001350671.1 transcript, we cannot exclude that the nucleotide sequence of the former leads to an in-frame transcript different from the predicted one by Battistini and Ricci (2020). Under this perspective, only protein studies will solve the issue.…”

“…Under this perspective, only protein studies will solve the issue. Battistini and Ricci (2020) also performed in silico splicing prediction of the two other missense variants reported in our manuscript (Nardella et al, 2018). Interestingly, the analysis showed that one of them [c.1048C>T, p.(Leu350Phe)] could affect the splicing process.…”

“…Response to: Concern regarding classification of c.703G>A/p.Gly235Arg as a novel missense variant in KRIT1 gene We appreciated the annotations by Battistini and Ricci (2020) on our paper (Nardella et al, 2018) and would like to take the opportunity to address the key concerns raised by the authors. We have considered their comments and, here, we tried to respond to them thoroughly.…”

“…Thanks to the annotation by Battistini and Ricci (2020), we recognized that the variant KRIT1 c.703G>A, p.(Gly235Arg) reported as ''novel'' in our manuscript (Nardella et al, 2018), has been previously published in (Cerase et al, 2010). We apologize for this mistake which was likely facilitated by the absence of the variant Such uncertainties on the potential effect of this variant on the splicing process prompt us to maintain prudence in assuming this variant as affecting splicing (i.e., splicing variant).…”