ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.2644G>A (p.Ala882Thr)

gnomAD frequency: 0.00001  dbSNP: rs767886377
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001211817 SCV001383376 benign Adams-Oliver syndrome 5 2022-07-26 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV002069303 SCV002495876 uncertain significance Aortic valve disease 1; Adams-Oliver syndrome 5 2021-03-30 criteria provided, single submitter clinical testing NOTCH1 NM_017617.4 exon 17 p.Ala882Thr (c.2644G>A): This variant has not been reported in the literature but is present in 0.001% (1/64566) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/9-136510749-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:941939). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Genome-Nilou Lab RCV001211817 SCV002553536 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002271194 SCV002553538 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002429900 SCV002743393 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-05-27 criteria provided, single submitter clinical testing The p.A882T variant (also known as c.2644G>A), located in coding exon 17 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 2644. The alanine at codon 882 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV004734049 SCV005353072 uncertain significance NOTCH1-related disorder 2024-07-26 no assertion criteria provided clinical testing The NOTCH1 c.2644G>A variant is predicted to result in the amino acid substitution p.Ala882Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations of uncertain and benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/941939/). At PreventionGenetics, this variant has been identified in multiple individuals tested for phenotypes not related to NOTCH1 disorders (Internal Data). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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