rs1555729604

chr19-15192449-G-Achr19-15192449-G-Cchr19-15192449-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000435.3(NOTCH3):c.268C>T(p.Arg90Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,164 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.57

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain in NM_000435.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 19-15192449-G-A is Pathogenic according to our data. Variant chr19-15192449-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 447816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.268C>T	p.Arg90Cys	missense_variant	3/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.268C>T	p.Arg90Cys	missense_variant	3/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.268C>T	p.Arg90Cys	missense_variant	3/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.265C>T	p.Arg89Cys	missense_variant	3/23	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460164 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 726358

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2020	The NOTCH3 c.268C>T; p.Arg90Cys variant has been described in several individuals and families affected with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome (Joutel 1997, Lackovic 2012, Lian 2013, Utku 2002). It contains an entry in ClinVar (Variation ID: 447816), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant lies within an EGF-like repeat domain, and pathogenic variants resulting in the gain or loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure (Dichgans 2000, Joutel 1997, Rutten 2016). Functional studies of the variant protein demonstrate reduced cell viability and aberrant NOTCH3 proteolytic processing in oligodendrocytes, and enhanced cortical susceptibility to spreading depression in mice (Eikermann-Haerter 2011, Tang 2017). Based on available information, this variant is considered pathogenic. REFERENCES Dichgans M et al. Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet. 2000 Apr;8(4):280-5. Eikermann-Haerter K et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression. Ann Neurol. 2011 Feb;69(2):413-8. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Lackovic V et al. Skin and sural nerve biopsies: ultrastructural findings in the first genetically confirmed cases of CADASIL in Serbia. Ultrastruct Pathol. 2012 Oct;36(5):325-35. Lian L et al. Spontaneous intracerebral hemorrhage in CADASIL. J Headache Pain. 2013 Dec 17;14:98. Rutten J et al. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain. 2016 Apr;139(Pt 4):1123-35. Tang M et al. CADASIL mutant NOTCH3(R90C) decreases the viability of HS683 oligodendrocytes via apoptosis. Mol Biol Rep. 2017 Jul;44(3):273-280. Utku U et al. CADASIL syndrome in a large Turkish kindred caused by the R90C mutation in the Notch3 receptor. Eur J Neurol. 2002 Jan;9(1):23-8. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 02, 2023	This variant has been identified in multiple unrelated individuals with clinical features associated with CADASIL. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 90 of the NOTCH3 protein (p.Arg90Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 9388399, 11784372, 23064698, 31813735). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447816). 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) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH3 protein function. Experimental studies have shown that this missense change affects NOTCH3 function (PMID: 14714274, 21387384, 23028706, 28601945). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 29, 2022	PP1, PP3, PP4, PM1, PM2, PS4 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Sep 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.89		Loss of MoRF binding (P = 0.0648);.;
MVP		1.0
MPC		1.2
ClinPred		0.90	D
GERP RS		4.1
Varity_R		0.20
gMVP		0.77

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

Other links and lift over

dbSNP: rs1555729604; hg19: chr19-15303260; COSMIC: COSV54629853;