Submissions for variant NM_024408.4(NOTCH2):c.2560T>C (p.Phe854Leu)

dbSNP: rs1650363387

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002273151	SCV002557813	uncertain significance	Hajdu-Cheney syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with Alagille syndrome 2 (MIM#610205), and Hajdu-Cheney syndrome (MIM#102500), respectively. Missense variants and those predicted to result in nonsense-mediated decay, have been associated with Alagille syndrome 2, whereas truncating variants in the last exon have been known to cause Hajdu-Cheney syndrome (OMIM, PMID: 28941602). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated EGF-like 22 domain (UniProt, DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0904 - Non-segregation of this variant with the phenotype under investigation has been clearly demonstrated. It has been found to be inherited from an unaffected mother. (SB) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003903658	SCV004718063	uncertain significance	NOTCH2-related disorder	2023-11-03	no assertion criteria provided	clinical testing	The NOTCH2 c.2560T>C variant is predicted to result in the amino acid substitution p.Phe854Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.