Submissions for variant NM_024408.4(NOTCH2):c.7223T>A (p.Leu2408His)

gnomAD frequency: 0.00228  dbSNP: rs35586704

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000121737	SCV000297311	likely benign	not specified	2015-12-17	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000121737	SCV000339428	likely benign	not specified	2016-02-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540032	SCV000636912	likely benign	Hajdu-Cheney syndrome	2025-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001711395	SCV001942685	benign	not provided	2021-01-21	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in possible association with primary ovarian insufficiency, congenital heart disease, and colorectal cancer (Patino et al., 2019; Patino et al., 2017; Priest et al., 2016; Timofeeva et al., 2015); Functional studies showed that p.L2408H did not demonstrate any significant change in NOTCH2 transcriptional activity compared with the wild type rates (Priest et al., 2016; Patino et al., 2019); This variant is associated with the following publications: (PMID: 28505269, 29089047, 30304577, 27058611, 26553438, 30651579, 33195954)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251991	SCV002523466	likely benign	See cases	2020-01-20	criteria provided, single submitter	clinical testing	ACMG classification criteria: BS1, BP4
Fulgent Genetics, Fulgent Genetics	RCV002498576	SCV002806272	benign	Alagille syndrome due to a NOTCH2 point mutation; Hajdu-Cheney syndrome	2021-10-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001711395	SCV004183575	benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	NOTCH2: BS1, BS2
ITMI	RCV000121737	SCV000085935	not provided	not specified	2013-09-19	no assertion provided	reference population
Clinical Genetics, Erasmus University Medical Center	RCV000508681	SCV000328906	uncertain significance	Hirschsprung disease, susceptibility to, 1	2016-11-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003975084	SCV004799000	likely benign	NOTCH2-related disorder	2019-05-22	no assertion criteria provided	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).