Submissions for variant NM_024408.4(NOTCH2):c.6007C>T (p.Arg2003Ter)

dbSNP: rs312262801

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000364519	SCV000345851	pathogenic	not provided	2017-03-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004955263	SCV005453413	likely pathogenic	Inborn genetic diseases	2024-11-15	criteria provided, single submitter	clinical testing	The c.6007C>T (p.R2003*) alteration, located in exon 33 (coding exon 33) of the NOTCH2 gene, consists of a C to T substitution at nucleotide position 6007. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 2003. This alteration occurs at the 3' terminus of the NOTCH2 gene and is not expected to trigger nonsense-mediated mRNA decay. for NOTCH2-related Alagille syndrome; however, its clinical significance for Hajdu-Cheney syndrome is uncertain This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in one individual and heterozygous in multiple individuals with liver pruritis, cholestasis, cardiac anomalies, butterfly-like vertebrae, typical facial features, small for gestational age, and/or other clinical features consistent with Alagille syndrome (Kamath, 2012; Lin, 2012; Alfares, 2017; Li, 2022; Ferrandino, 2024). In an assay testing NOTCH2 function, this variant showed a functionally abnormal result (Kamath, 2012). Based on the available evidence, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089336	SCV005833929	pathogenic	Hajdu-Cheney syndrome	2024-09-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2003*) in the NOTCH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 469 amino acid(s) of the NOTCH2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Alagille syndrome (PMID: 22209762). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 41266). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NOTCH2 function (PMID: 22209762). For these reasons, this variant has been classified as Pathogenic.