rs1438626607

Variant names:

• chr19-15180173-G-A
• rs1438626607
• NM_000435.3:c.3226C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000435.3(NOTCH3):​c.3226C>T​(p.Arg1076Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1076H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.79
• Publications: 11 publications found

Genes affected

NOTCH3 (HGNC:7883): (notch receptor 3) This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

NOTCH3 Gene-Disease associations (from GenCC):

• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• lateral meningocele syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• infantile myofibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myofibromatosis, infantile, 2

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 19-15180173-G-A is Pathogenic according to our data. Variant chr19-15180173-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 447830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000435.3. 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
	NOTCH3	NM_000435.3	MANE Select	c.3226C>T	p.Arg1076Cys	missense	Exon 20 of 33	NP_000426.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH3	ENST00000263388.7	TSL:1 MANE Select	c.3226C>T	p.Arg1076Cys	missense	Exon 20 of 33	ENSP00000263388.1
	NOTCH3	ENST00000601011.1	TSL:5	c.3067C>T	p.Arg1023Cys	missense	Exon 19 of 23	ENSP00000473138.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461524 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727068

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111888

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152026 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74220

African (AFR) AF: 0.00 AC: 0 AN: 41370

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Feb 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NOTCH3 c.3226C>T; p.Arg1076Cys variant (rs1438626607) is reported in the literature in several individuals and families affected with CADASIL (Dotti 2005, Juhosova 2023, Lesnik Oberstein 2003, Liao 2015, Mosca 2011, Ni 2022, Pantoni 2010, Piccirillo 2008, Uemura 2023). This variant is reported in ClinVar (Variation ID: 447830). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.663). However, this variant occurs in an EGF-like domain, and most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). Based on available information, this variant is considered to be likely pathogenic. References: Dotti MT et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry. 2005 May;76(5):736-8. PMID: 15834039. Juhosova M et al. Influence of different spectra of NOTCH3 variants on the clinical phenotype of CADASIL - experience from Slovakia. Neurogenetics. 2023 Jan;24(1):1-16. PMID: 36401683. Lesnik Oberstein SA et al. Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Medicine (Baltimore). 2003 Jul;82(4):251-6. PMID: 12861102. Liao YC et al. Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles. PLoS One. 2015 Aug 26;10(8):e0136501. PMID: 26308724. Mosca L et al. NOTCH3 gene mutations in subjects clinically suspected of CADASIL. J Neurol Sci. 2011 Aug 15;307(1-2):144-8. PMID: 21616505. Ni W et al. Genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients in different populations. CNS Neurosci Ther. 2022 Nov;28(11):1779-1789. PMID: 35822697. Pantoni L et al. Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients. Neurology. 2010 Jan 5;74(1):57-63. PMID: 20038773. Piccirillo G et al. Increased QT variability in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Eur J Neurol. 2008 Nov;15(11):1216-21. PMID: 18803652. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. PMID: 24844136. Uemura M et al. High frequency of HTRA1 AND ABCC6 mutations in Japanese patients with adult-onset cerebral small vessel disease. J Neurol Neurosurg Psychiatry. 2023 Jan;94(1):74-81. PMID: 36261288.

Mar 21, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with CADASIL. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of pathogenic variants identified in NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain.

Jun 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1076 of the NOTCH3 protein (p.Arg1076Cys). This variant is present in population databases (no rsID available, gnomAD 0.06%). This missense change has been observed in individuals with autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (PMID: 11571335, 12861102, 15827866, 15834039, 22878905; Invitae). This variant is also known as R1075C. ClinVar contains an entry for this variant (Variation ID: 447830). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. For these reasons, this variant has been classified as Pathogenic.

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOTCH3: PM1:Strong, PM2, PS4:Moderate, PP2

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Pathogenic:2

Aug 21, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.66 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.90 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000447830 /PMID: 12861102).The variant has been observed in at least two similarly affected unrelated individuals (PMID: 11571335, 12861102, 15827866, 15834039, 22878905). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Feb 21, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4_MOD,PM1,PM2,PP2,PP3.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.83		Loss of phosphorylation at S1079 (P = 0.0693)
MVP		1.0
MPC		1.4
ClinPred		0.91	D
GERP RS		4.8
Varity_R		0.20
gMVP		0.75
Mutation Taster		=12/88	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: rs1438626607; hg19: chr19-15290984; COSMIC: COSV54643699; COSMIC: COSV54643699;