Submissions for variant NM_022455.4(NSD1):c.7180A>G (p.Ile2394Val) (rs1554207690)

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Total submissions: 1

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000628535	SCV000749437	likely pathogenic	Beckwith-Wiedemann syndrome	2019-05-10	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with valine at codon 2394 of the NSD1 protein (p.Ile2394Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with a NSD1-related disease (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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