Submissions for variant NM_024408.4(NOTCH2):c.1804G>A (p.Ala602Thr)

gnomAD frequency: 0.00039  dbSNP: rs140311741

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595171	SCV000705754	uncertain significance	not provided	2018-05-22	criteria provided, single submitter	clinical testing
Invitae	RCV000693115	SCV000820970	likely benign	Hajdu-Cheney syndrome	2023-12-30	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000595171	SCV001762345	likely benign	not provided	2021-07-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952977	SCV004770952	likely benign	NOTCH2-related condition	2022-03-04	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000595171	SCV001549681	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NOTCH2 p.Ala602Thr variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs140311741), LOVD 3.0 and in ClinVar (classified as a VUS for Hajdu-Cheney syndrome by Invitae and EGL Genetics). The variant was identified in control databases in 85 of 282500 chromosomes at a frequency of 0.000301 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 78 of 128854 chromosomes (freq: 0.000605), Other in 2 of 7220 chromosomes (freq: 0.000277), African in 2 of 24964 chromosomes (freq: 0.00008), Latino in 2 of 35430 chromosomes (freq: 0.000056) and European (Finnish) in 1 of 25124 chromosomes (freq: 0.00004); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Ala602 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000595171	SCV001799161	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000595171	SCV001952105	likely benign	not provided		no assertion criteria provided	clinical testing