Submissions for variant NM_024408.4(NOTCH2):c.6767G>A (p.Arg2256His)

gnomAD frequency: 0.00004  dbSNP: rs148759277

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000591307	SCV000705578	uncertain significance	not provided	2017-10-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000591307	SCV001249624	uncertain significance	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001254708	SCV001430777	uncertain significance	Congenital anomaly of kidney and urinary tract	2020-05-28	criteria provided, single submitter	research	The heterozygous p.Arg2256His variant in NOTCH2 was identified by our study in 1 individual with renal or urinary tract malformation (CAKUT) and in this individuals father whose affection status is unknown. It is of note that reduced penetrance has been previously described in CAKUT (PMID: 29293093). The p.Arg2256His variant in NOTCH2 has been reported in this same individual, segregated with disease in 3 affected relatives from 1 family (PMID: 30143558), and has been identified in 0.01% (2/19952) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148759277). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg2256His variant is uncertain. ACMG/AMP Criteria applied: none (Richards 2015).
Baylor Genetics	RCV001336625	SCV001530055	uncertain significance	Hajdu-Cheney syndrome	2018-09-26	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV002476309	SCV002790089	uncertain significance	Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome	2021-11-17	criteria provided, single submitter	clinical testing
Invitae	RCV001336625	SCV004277019	uncertain significance	Hajdu-Cheney syndrome	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2256 of the NOTCH2 protein (p.Arg2256His). This variant is present in population databases (rs148759277, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of NOTCH2-related conditions (PMID: 30143558). ClinVar contains an entry for this variant (Variation ID: 499864). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOTCH2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003952975	SCV004775555	uncertain significance	NOTCH2-related disorder	2024-01-31	criteria provided, single submitter	clinical testing	The NOTCH2 c.6767G>A variant is predicted to result in the amino acid substitution p.Arg2256His. This variant has been reported in an individual with congenital anomalies of the kidney and urinary tract (van der Ven et al. 2018. PubMed ID: 30143558). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.