ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4426G>A (p.Gly1476Ser) (rs776133530)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521514 SCV000619741 uncertain significance not provided 2017-08-04 criteria provided, single submitter clinical testing The G1476S variant in the NOTCH1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge; however, the G1476S variant was reported among the control population in a study of individuals with left ventricular outflow tract defects and NOTCH1 variants (McBride et al., 2008). Additionally, a missense variant at this same codon (G1476D) was reported in a child with hypoplastic left heart syndrome as well as in the individual's healthy mother, and the affected individual was also reported to have a paternally inherited partial duplication of the ZNF423 gene (Iascone et al., 2012). The G1476S variant is observed in 4/64664 (0.01%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The G1476S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G1476S as a variant of uncertain significance.

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