rs797045014

chr19-15192182-G-Achr19-15192182-G-Cchr19-15192182-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000435.3(NOTCH3):c.457C>T(p.Arg153Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,218 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. R153H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.85

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 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000435.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-15192181-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2572610.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 19-15192182-G-A is Pathogenic according to our data. Variant chr19-15192182-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15192182-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.457C>T	p.Arg153Cys	missense_variant	4/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.457C>T	p.Arg153Cys	missense_variant	4/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.457C>T	p.Arg153Cys	missense_variant	4/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.454C>T	p.Arg152Cys	missense_variant	4/23	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460218 Hom.: 0 Cov.: 40 AF XY: 0.00000138 AC XY: 1 AN XY: 726440

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 153 of the NOTCH3 protein (p.Arg153Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CADASIL (PMID: 9388399, 10802804, 16193256, 27890607). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208501). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 12, 2022	This variant has been identified in multiple unrelated individuals with clinical features of CADASIL. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2022	The NOTCH3 c.457C>T; p.Arg153Cys variant (rs797045014) is reported in the literature in multiple individuals affected with CADASIL (Ceroni 2000, Joutel 1997, Konialis 2007, Mandellos 2005, Matsushima 2017, Tarzjani 2018). This variant is reported as pathogenic in ClinVar (Variation ID: 208501), 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 153 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This variant lies with 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 2007, Rutten 2016). Based on available information, the p.Arg153Cys variant is considered to be pathogenic. References: Ceroni M et al. Migraine with aura and white matter abnormalities: Notch3 mutation. Neurology. 2000 May 9;54(9):1869-71. 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. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Konialis C et al. Pregnancy following preimplantation genetic diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Prenat Diagn. 2007 Nov;27(11):1079-83. Mandellos D et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a Greek family. Neurol Sci. 2005 Oct;26(4):278-81. Matsushima T et al. Genotype-phenotype correlations of cysteine replacement in CADASIL. Neurobiol Aging. 2017 Feb;50:169.e7-169.e14. Rutten JW et al. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain. 2016 Apr;139(Pt 4):1123-35. Tarzjani SPC et al. Genetic study of the NOTCH3 gene in CADASIL patients. Egypt J Med Hum Genet. 2018 Oct;19(4):425-7. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32277177, 31915071, 31680059, 32470649, 30956055, 31584664, 17729386, 10802804, 27890607, 9388399, 16193256) -

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

Pathogenic, no assertion criteria provided	clinical testing	Mendelics	Apr 22, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.457C>T;p.(Arg153Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar: 208501; PMID: 27206574; 28710804; 31915071; 32457593) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (EGF) - PM1. This variant is not present in population databases (rs797045014, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in NOTCH3 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Transient ischemic attack;C0948008:Ischemic stroke Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Pathogenic	0.78
Sift	Benign	0.042	D;.
Sift4G	Uncertain	0.048	D;D
Polyphen		0.99	D;.
Vest4		0.66
MutPred		0.89		Loss of phosphorylation at S154 (P = 0.0681);.;
MVP		0.99
MPC		1.4
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.53
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs797045014; hg19: chr19-15302993;