19-15180807-G-A

Position:

• chr19-15180807-G-A

Variant summary

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

The ENST00000263388.7(NOTCH3):​c.3016C>T​(p.Arg1006Cys) 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 1,459,666 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1006R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NOTCH3 ENST00000263388.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 0.852

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000263388.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 19-15180807-G-A is Pathogenic according to our data. Variant chr19-15180807-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 447823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15180807-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.3016C>T	p.Arg1006Cys	missense_variant	19/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.2860C>T	p.Arg954Cys	missense_variant	18/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.3016C>T	p.Arg1006Cys	missense_variant	19/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000601011.1	c.2857C>T	p.Arg953Cys	missense_variant	18/23	5		ENSP00000473138

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459666 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725916

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1006 of the NOTCH3 protein (p.Arg1006Cys). 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, 15834039, 19576955, 23412372, 33020014). It has also been observed to segregate with disease in related individuals. This variant is also known as C3094T. ClinVar contains an entry for this variant (Variation ID: 447823). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NOTCH3 function (PMID: 14714274). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	The NOTCH3 c.3016C>T; p.Arg1006Cys variant (rs1555727942) is reported in the literature in several individuals affected with CADASIL (Cappelli 2009, Gonzalez 2020, Hu 2021, Joutel 1997, Ni 2022). This variant is also reported in ClinVar (Variation ID: 447823), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.569). However, 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 this variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be pathogenic. References: Cappelli A et al. High recurrence of the R1006C NOTCH3 mutation in central Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neurosci Lett. 2009 Sep 22;462(2):176-8. PMID: 19576955. Gonzalez F et al. Non-convulsive status epilepticus as the initial manifestation in a family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neurologia (Engl Ed). 2020 Oct 2:S0213-4853(20)30214-0. English, Spanish. PMID: 33020014. Hu Y et al. NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients. Front Genet. 2021 Jul 15;12:705284. PMID: 34335700. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. PMID: 9388399. 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. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 10, 2023	This variant has been identified in multiple unrelated individuals with CADASIL. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.3094C>T; p.Arg1006Cys. 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). -

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

not provided, no classification provided

literature only

GeneReviews

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.93	D;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	-0.069	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.93	D
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.029	D;.
Sift4G	Uncertain	0.021	D;D
Polyphen		0.99	D;.
Vest4		0.16
MutPred		0.84		Loss of solvent accessibility (P = 0.1077);.;
MVP		0.98
MPC		0.59
ClinPred		0.86	D
GERP RS		2.9
Varity_R		0.22
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

Other links and lift over

dbSNP: rs1555727942; hg19: chr19-15291618; COSMIC: COSV54639336; COSMIC: COSV54639336;