1-119915812-TG-TGG

Variant names:

• chr1-119915812-T-TG
• rs771237928
• NM_024408.4:c.6909dupC

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_024408.4(NOTCH2):​c.6909dupC​(p.Ile2304HisfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P2303P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOTCH2 NM_024408.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.135
• Publications: 19 publications found

Genes affected

NOTCH2 (HGNC:7882): (notch receptor 2) This gene encodes a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between physically adjacent cells. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remain to be determined. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. This protein functions as a receptor for membrane bound ligands, and may play a role in vascular, renal and hepatic development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

NOTCH2 Gene-Disease associations (from GenCC):

• acroosteolysis dominant type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Alagille syndrome due to a NOTCH2 point mutation

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Alagille syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-119915812-T-TG is Pathogenic according to our data. Variant chr1-119915812-T-TG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 223003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024408.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	NM_024408.4	MANE Select	c.6909dupC	p.Ile2304HisfsTer9	frameshift	Exon 34 of 34	NP_077719.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	ENST00000256646.7	TSL:1 MANE Select	c.6909dupC	p.Ile2304HisfsTer9	frameshift	Exon 34 of 34	ENSP00000256646.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hajdu-Cheney syndrome Pathogenic:2

May 22, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID:27312922). The variant has been reported to be associated with NOTCH2- related disorder (ClinVar ID: VCV000223003 / PMID: 27312922). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

Sep 29, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a premature translational stop signal in the NOTCH2 gene (p.Ile2304Hisfs*9). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 168 amino acids 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 ExAC database. This variant has been reported to be de novo in an individual affected with Hajdu-Cheney syndrome (HCS) (PMID: 27312922). Multiple truncating variants in the last exon of NOTCH2 have been reported in individuals with HCS resulting in deletion of the PEST (proline(P), glutamic acid(E), serine(S), threonine(T)) domain at the C-terminus which regulates the Notch intracellular domain (NICD) with ankyrin repeats (PMID: 21378989, 21378985, 8755249). Specifically, PEST domains are implicated in mediating proteosomal degradation of proteins with ankyrin-repeat domains, and loss of this PEST domain is expected to result in a stable, functional but constitutively active NICD in the NOTCH2 protein (PMID: 21378989, 8755249). For these reasons, this variant has been classified as Pathogenic.

Monoclonal B-Cell Lymphocytosis Pathogenic:1

Dec 15, 2015

Karsan Lab, BC Cancer Agency

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

not provided Pathogenic:1

Jul 10, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant in the last exon of NOTCH2 predicted to result in protein truncation, as the last 168 amino acids are replaced with 8 different amino acids; protein-truncating or frameshift variants that remove or disrupt the PEST domain sequence are predicted to result in a gain-of-function and are associated with HCS/SFPKS (PMID: 21378985, 27241678); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21378985, 27241678, 22891276, 25141821, 30534535, 29618366, 34586000, 32145092, 33520214, 36232677, 27312922)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771237928; hg19: chr1-120458435; COSMIC: COSV56681310;