Submissions for variant NM_024408.4(NOTCH2):c.7198C>T (p.Arg2400Ter)

gnomAD frequency: 0.00001  dbSNP: rs1325403451

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion, Medical Genetics	RCV000617014	SCV002521744	pathogenic	Hajdu-Cheney syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported to be associated with NOTCH2 related disorder (ClinVar ID: VCV000518450 / PMID: 21378985). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV002508237	SCV002818083	pathogenic	not provided	2022-12-30	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 72 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 24296945, 21378985, 25141821, 24995648, 29453417, 29698804, 32978145, 31785789, 29618366, 24077912, 23389697, 28832562, 21793104, 33448881, 25590979)
Baylor Genetics	RCV000617014	SCV004041181	pathogenic	Hajdu-Cheney syndrome	2023-02-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000617014	SCV004291983	pathogenic	Hajdu-Cheney syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2400*) in the NOTCH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 72 amino acid(s) of the NOTCH2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Hajdu-Cheney syndrome (PMID: 21378985, 29698804). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 518450). This protein change is located in a region of the NOTCH2 protein where a significant number of previously reported NOTCH2 nonsense and frameshift mutations are found (PMID: 21378985, 23389697, 26627824). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760646	SCV005368167	pathogenic	Alagille syndrome due to a NOTCH2 point mutation	2022-03-08	criteria provided, single submitter	clinical testing
Metabolic Disease laboratory, Sheba Medical Center	RCV000617014	SCV000734848	pathogenic	Hajdu-Cheney syndrome	2017-10-01	no assertion criteria provided	clinical testing