rs777751303

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_000435.3(NOTCH3):c.1819C>T(p.Arg607Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,928 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. R607H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 0.320

Publications

34 publications found

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 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

NOTCH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000435.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

PP5

Variant 19-15187126-G-A is Pathogenic according to our data. Variant chr19-15187126-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374637.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
NOTCH3	NM_000435.3 link	c.1819C>T	p.Arg607Cys	missense_variant	Exon 11 of 33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 link	c.1819C>T	p.Arg607Cys	missense_variant	Exon 11 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 link	c.1819C>T	p.Arg607Cys	missense_variant	Exon 11 of 33	1	NM_000435.3	ENSP00000263388.1		Q9UM47
NOTCH3	ENST00000601011.1 link	c.1816C>T	p.Arg606Cys	missense_variant	Exon 11 of 23	5		ENSP00000473138.1		M0R3C9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250118

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000496

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NOTCH3 c.1819C>T; p.Arg607Cys variant (rs777751303), also known as 1897C>T; R607C, is reported in the literature in numerous individuals and families affected with CADASIL (Dotti 2005, Escary 2000, Hu 2021, Mukai 2020, Qin 2019, Singhal 2004, Watanabe 2012). This variant is reported in ClinVar (Variation ID: 374637), and it is only observed on only one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 607 is highly conserved and occurs in an EGF-like domain, and computational analyses predict that this variant is deleterious (REVEL: 0.709). Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), and thus the p.Arg607Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be 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. Escary JL et al. Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. Hum Mutat. 2000 Dec;16(6):518-26. PMID: 11102981. Hu Y et al. NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients. Front Genet. 2021 Jul 15;12:705284. PMID: 34335700. Mukai et al. Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients. J Hum Genet. 2020 Aug;65(8):637-646. PMID: 32277177. Qin W et al. Clinical Features of 4 Novel NOTCH3 Mutations of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy in China. Med Sci Monit Basic Res. 2019 Sep 26;25:199-209. PMID: 31554780. 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. Singhal S et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004 Sep;127(Pt 9):2031-8. PMID: 15229130. Watanabe M et al. An unusual case of elderly-onset cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with multiple cerebrovascular risk factors. J Stroke Cerebrovasc Dis. 2012 Feb;21(2):143-5. PMID: 20851625. -

Feb 29, 2024

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 clinical features associated 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 NOTCH3 pathogenic variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673). -

Oct 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 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 607 of the NOTCH3 protein (p.Arg607Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with CADASIL (PMID: 15834039, 20851625, 20935329, 31554780). ClinVar contains an entry for this variant (Variation ID: 374637). 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. -

May 21, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12395806, 18948701, 11102981, 20935329, 22664156, 19080749, 15229130, 22367627, 19542611, 12821764, 31589614, 31915071, 28991717, 37681004, 30956055, 37479695, 22878905, 16367901, 15827866, 30311053, 33942994, 35754959, 31996268, 36221938, 33597917, 27844030, 37526664, YangCY2022[CaseReport], TalayaNavarro2023[CaseReport], 15834039, 34741685, 24139282, 25344745, 32277177, 35822697, 31554780, 34335700, 34851492, 36047879, 12756589, 28710804, 36261288, 20851625, 20123231, 31028544, 24844136) -

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

Pathogenic:2Other:1

Sep 03, 2021

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change in NOTCH3 is predicted to replace arginine with cysteine at codon 607 (p.(Arg607Cys)). The arginine residue is moderately conserved (100 vertebrates, UCSC), and introduces an odd number of cysteine residues in EGF-like repeat domain 15 (expected to alter the disulphide bonds in this domain). There is a large physicochemical difference between arginine and cysteine. This variant is present in a single East Asian individual in gnomAD v2.1 (1/109,194 alleles), which is still a plausible population frequency for a dominant condition. This variant has been reported in at least 16 probands/families with a clinical diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and is an international recurrent mutation (PMID: 11102981, 12821764, 15229130, 15834039, 28710804, 28991717). The variant has been reported to segregate with CADASIL in multiple families (PMID: 28710804). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/5 algorithms deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS4_VeryStrong, PP1_Strong, PM1,PM2_Supporting. -

GenomeConnect - CureCADASIL

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Pathogenic and reported on 06-15-2022 by Lab or GTR ID 25969. 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. -

Jan 07, 2025

Department of Human Genetics, Hannover Medical School

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG: PM1_Supporting, PM2_Supporting, PP1_Strong, PP3, PP4 -

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

Pathogenic:1

Oct 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;D

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.68

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

0.32

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.4

N;.

REVEL

Pathogenic

0.71

Sift

Benign

0.17

T;.

Sift4G

Benign

0.17

T;T

Polyphen

0.99

D;.

Vest4

0.79

MutPred

0.87

Gain of ubiquitination at K603 (P = 0.0513);.;

MVP

1.0

MPC

1.4

ClinPred

0.84

GERP RS

3.2

Varity_R

0.28

gMVP

0.77

Mutation Taster

=29/71

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over