rs1554826746

Variant names:

• chr9-136499244-G-A
• rs1554826746
• NM_017617.5:c.5950C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136499244-G-A
• chr9-136499244-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017617.5(NOTCH1):​c.5950C>T​(p.Arg1984*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1984R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: NOTCH1 NM_017617.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.95
• Publications: 0 publications found

Genes affected

NOTCH1 (HGNC:7881): (notch receptor 1) This gene encodes a member of the NOTCH family of proteins. Members of this Type I 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 signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

NOTCH1 Gene-Disease associations (from GenCC):

• Adams-Oliver syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• Adams-Oliver syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• aortic valve disease 1

  Inheritance: AD Classification: STRONG Submitted by: G2P, PanelApp Australia
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leukodystrophy

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-136499244-G-A is Pathogenic according to our data. Variant chr9-136499244-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 520784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.5950C>T	p.Arg1984*	stop_gained	Exon 32 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.5227C>T	p.Arg1743*	stop_gained	Exon 29 of 31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.5950C>T	p.Arg1984*	stop_gained	Exon 32 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NOTCH1-related disorder Pathogenic:1

Apr 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2 -

Inborn genetic diseases Pathogenic:1

Sep 22, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KA-like vemurafenib-induced squamous lesions Pathogenic:1

Jun 07, 2016

Yale Center for Mendelian Genomics, Yale University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26820064, 27283355, 37839360) -

Aortic valve disease 1 Pathogenic:1

Nov 14, 2023

Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not present in the general population (gnomAD). It is not listed in the dbSNP151 database. The variant has been reported twice as pathogenic in the ClinVar database (Variation ID 520784), but without a phenotypic description or in a different clinical context. In the literature, the variant has already been reported in a patient with aortic valve stenosis and a thoracic aortic aneurysm. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	50
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		1.9
Vest4		0.99
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=3/197	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: rs1554826746; hg19: chr9-139393696; COSMIC: COSV53039810; COSMIC: COSV53039810;