rs137852642

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000435.3(NOTCH3):c.397C>T(p.Arg133Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,026 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18O:2

Conservation

PhyloP100: 3.36

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a disulfide_bond (size 11) in uniprot entity NOTC3_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000435.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 19-15192242-G-A is Pathogenic according to our data. Variant chr19-15192242-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15192242-G-A is described in Lovd as [Pathogenic]. Variant chr19-15192242-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.397C>T	p.Arg133Cys	missense_variant	Exon 4 of 33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 link	c.397C>T	p.Arg133Cys	missense_variant	Exon 4 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 link	c.397C>T	p.Arg133Cys	missense_variant	Exon 4 of 33	1	NM_000435.3	ENSP00000263388.1		Q9UM47
NOTCH3	ENST00000601011.1 link	c.394C>T	p.Arg132Cys	missense_variant	Exon 4 of 23	5		ENSP00000473138.1		M0R3C9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000451

AC:

AN:

221490

Hom.:

AF XY:

0.00000829

AC XY:

AN XY:

120636

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000517

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1450026

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720456

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000387

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:9Other:2

GenomeConnect - CureCADASIL

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and most recently reported on 09-17-2018 by Lab or GTR ID 1012. Variant also interpreted as Pathogenic and reported on 05-12-2019 by GTR ID 500035. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -

Apr 20, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.397C>T(p.Arg133Cys) in NOTCH3 gene has been reported in heterozygous state in individuals affected with CADSIL (Li J, et. al.,2022; Mönkäre S, et. al., 2022).Experimental studies suggests that the variant causes protein aggregation and ER retention, resulting in impaired cell proliferation (Schoemaker D, et. al., 2021). This variant is present with an allele frequency of 0.0004% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Likely pathogenic/Pathogenic (multiple submission). The amino acid change p.Arg133Cys in NOTCH3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 133 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT -probably Damaging, and MutationTaster - disease causing automatic) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -

Aug 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NOTCH3 c.397C>T (p.Arg133Cys) results in a non-conservative amino acid change located in the EGF like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-06 in 221490 control chromosomes. c.397C>T has been reported in the literature in multiple individuals affected with Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (example: Mukai_2020). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 32277177). ClinVar contains an entry for this variant (Variation ID: 9225). Based on the evidence outlined above, the variant was classified as pathogenic. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PP2, PP3, PP5 -

Dec 21, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP2,PP3. -

Feb 05, 2024

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: <0.001%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19825845). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.86 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.84 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000009225 /PMID: 9388399) and different missense changes at the same codon (p.Arg133Leu, p.Arg133Ser / ClinVar ID: VCV001687327 /PMID: 34335700) have been previously reported as pathogenic/likely pathogenic with strong evidence.The variant has been observed in at least two similarly affected unrelated individuals (PMID: 10969905, 28334938). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:6

Nov 20, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4, PP5, PM1, PS3, PS4 -

Feb 28, 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 (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in at least one individual with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant causes protein aggregation and ER retention, resulting in impaired cell proliferation (PMID: 19825845). 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. -

Aug 31, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest that the R133C impacts protein function (Opherk et al., 2009; Takahashi et al., 2010; Wollenweber et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10854111, 26261665, 11771160, 25819272, 15378071, 15364702, 16009764, 9388399, 15350543, 19417009, 19825845, 10969905, 11715067, 15716553, 22623959, 22019870, 11486103, 25604251, 28334938, 28534048, 10371548, 12810003, 11755616, 31571467, 31554780, 30402942, 31720972, 34335700, 34008892, 15143298, 10609671, 36047879, 32555735, 34741685, 10766655, 30392756, 16877080, 32277177, 24844136) -

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NOTCH3 c.397C>T; p.Arg133Cys variant (rs137852642) has been described in multiple individuals affected with CADASIL (Joutel 1997, Maclean 2005, Mykkanen 2004). This variant is reported as pathogenic or likely pathogenic in ClinVar (Variation ID: 9225), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 133 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In vitro characterization of this variant protein demonstrates increased spontaneous multimerization compared to wild-type (Opherk 2009). Based on available information, this variant is considered to be pathogenic. References: Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Maclean A et al. Spontaneous lobar haemorrhage in CADASIL. J Neurol Neurosurg Psychiatry. 2005 Mar;76(3):456-7. Mykkanen K et al. Detection of the founder effect in Finnish CADASIL families. Eur J Hum Genet. 2004 Oct;12(10):813-9. Opherk C et al. CADASIL mutations enhance spontaneous multimerization of NOTCH3. Hum Mol Genet. 2009 Aug 1;18(15):2761-7. -

Jan 22, 2025

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 133 of the NOTCH3 protein (p.Arg133Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CADASIL (PMID: 10969905, 22019870, 28334938). ClinVar contains an entry for this variant (Variation ID: 9225). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NOTCH3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Recurrent subcortical infarcts

Pathogenic:1

Nov 28, 2013

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NOTCH3-related disorder

Pathogenic:1

Jul 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NOTCH3 c.397C>T variant is predicted to result in the amino acid substitution p.Arg133Cys. This variant has been reported as causative for CADASIL in numerous affected individuals and its pathogenicity is supported by functional studies (Joutel et al. 1997. PubMed ID: 9388399; Wollenweber et al. 2015. PubMed ID: 25604251). Of note, the vast majority of CADASIL-causing variants in the NOTCH3 gene are predicted to result in the gain or loss of cysteine residues in the extracellular domain of the protein, as seen in this patient. At PreventionGenetics, we have previously detected this variant in other affected individuals. This variant is reported in 0.0052% of alleles in individuals of European (Finnish) descent in gnomAD and is interpreted as pathogenic/likely pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/9225/). This variant is interpreted as pathogenic. -

Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Pathogenic:1

Apr 27, 2020

North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria Codes: PS3_Str PS4_Mod PM1_Str PP1_Str PP2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.32

T;T

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.7

L;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.7

D;.

REVEL

Pathogenic

0.86

Sift

Benign

0.046

D;.

Sift4G

Uncertain

0.052

T;D

Polyphen

0.99

D;.

Vest4

0.71

MutPred

0.84

Gain of catalytic residue at S135 (P = 0.064);.;

MVP

1.0

MPC

1.4

ClinPred

0.96

GERP RS

5.0

Varity_R

0.63

gMVP

0.71

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over