Submissions for variant NM_017617.5(NOTCH1):c.2326G>A (p.Val776Met) (rs377286829)

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Total submissions: 1

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000527166	SCV000659398	uncertain significance	Adams-Oliver syndrome 5	2017-07-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine with methionine at codon 776 of the NOTCH1 protein (p.Val776Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs377286829, ExAC 0.01%). This variant has not been reported in the literature in individuals with NOTCH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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