ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.1981G>A (p.Gly661Ser) (rs201077220)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000251143 SCV000320542 uncertain significance Cardiovascular phenotype 2018-02-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000519623 SCV000617311 uncertain significance not provided 2018-05-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The G661S variant has been reported in 4/91 individuals with left ventricular outflow tract malformations (LVOT), though one individual harbored a second R1279H variant in cis (McBride et al., 2008). In addition, G661S was identified in 1/212 ethnically matched controls (McBride et al., 2008). This variant was also observed in 2/1006 (0.2%) European alleles in 1000 Genomes project and in 39/65516 (0.06%) European alleles in the Exome Aggregation Consortium. The G661S 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 across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies showed that the G661S variant was associated with reduced ligand-induced Notch1 signalling, possibly due to reduced cell surface expression; however, a specific mechanism was not established and it is not known whether the experimental conditions represent the physiologic effect of the variant in vivo (McBride et al., 2008; Riley et al., 2011). Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with NOTCH1-related disorders (Stenson et al., 2014).
Invitae RCV000555279 SCV000659386 uncertain significance Adams-Oliver syndrome 5 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 661 of the NOTCH1 protein (p.Gly661Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs201077220, ExAC 0.06%). This variant has been reported in the literature in 4 individuals affected with congenital cardiovascular malformations involving the left ventricular outflow tract as well as in one healthy control individual (PMID: 18593716). ClinVar contains an entry for this variant (Variation ID: 264541). Experimental studies have shown that this missense change decreases ligand induced signaling compared to wild-type (PMID: 18593716, 20951801). In summary, this variant is a rare missense change that has been shown to have a deleterious effect in protein function. However, it is found in the population at a higher frequency than expected for pathogenic variants. The available evidence is insufficient to determine whether this variant is causative or not. Therefore, it has been classified as a Variant of Uncertain Significance.

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