Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000538087 | SCV000659419 | uncertain significance | Adams-Oliver syndrome 5 | 2019-05-17 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid with asparagine at codon 1064 of the NOTCH1 protein (p.Asp1064Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs375931404, ExAC 0.03%) but has not been reported in the literature in individuals with a NOTCH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Integrated Genetics/Laboratory Corporation of America | RCV001201312 | SCV001372451 | uncertain significance | not specified | 2020-06-25 | criteria provided, single submitter | clinical testing | Variant summary: NOTCH1 c.3190G>A (p.Asp1064Asn) results in a conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 248542 control chromosomes. To our knowledge, no occurrence of c.3190G>A in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |