Submissions for variant NM_017617.5(NOTCH1):c.1237G>A (p.Val413Met) (rs373770404)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000700880	SCV000829656	uncertain significance	Adams-Oliver syndrome 5	2019-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine with methionine at codon 413 of the NOTCH1 protein (p.Val413Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs373770404, ExAC 0.02%). This variant has not been reported in the literature in individuals with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 578001). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000769608	SCV000901005	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-09-26	criteria provided, single submitter	clinical testing

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