ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.3835C>T (p.Arg1279Cys) (rs182330532)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001088972 SCV000290270 likely benign Adams-Oliver syndrome 5 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000246340 SCV000319648 uncertain significance Cardiovascular phenotype 2018-03-20 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000484160 SCV000569748 uncertain significance not provided 2018-09-25 criteria provided, single submitter clinical testing The R1279C variant in the NOTCH1 gene has been reported previously in a three-generation kindred with congenital heart defects, in which the R1279C variant segregated with disease in multiple relatives, though it was also identified in one family member with a normal echocardiogram (Blue et al., 2017). This variant is also observed in 19/10,008 alleles (0.2%) from individuals of Ashkenazi Jewish background, and 98/269,088 global alleles (0.04%), in large population cohorts (Lek et al., 2016). The R1279C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, in vitro functional anlysis of mouse myoblast cells showed no significant change in NOTCH1 signaling in the presence of the R1279C variant (Blue et al., 2017). We interpret R1279C as a variant of uncertain significance.

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