rs863225297

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000435.3(NOTCH3):​c.1187C>G​(p.Ser396Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

NOTCH3
NM_000435.3 missense

Scores

11
6
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.58
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1
In a domain EGF-like 10; calcium-binding (size 38) in uniprot entity NOTC3_HUMAN there are 9 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, 0.896
PP5
Variant 19-15189278-G-C is Pathogenic according to our data. Variant chr19-15189278-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 217882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOTCH3NM_000435.3 linkc.1187C>G p.Ser396Cys missense_variant 7/33 ENST00000263388.7 NP_000426.2 Q9UM47
NOTCH3XM_005259924.5 linkc.1187C>G p.Ser396Cys missense_variant 7/32 XP_005259981.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOTCH3ENST00000263388.7 linkc.1187C>G p.Ser396Cys missense_variant 7/331 NM_000435.3 ENSP00000263388.1 Q9UM47
NOTCH3ENST00000601011.1 linkc.1184C>G p.Ser395Cys missense_variant 7/235 ENSP00000473138.1 M0R3C9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingMendelicsJul 25, 2014- -
Pathogenic, criteria provided, single submitterclinical testingDASASep 02, 2021The c.1187C>G;p.(Ser396Cys) variant has been published as a pathogenic variant in individuals affected with CADASIL, described with possible effect founder in italian population (PMID: 22664156; GeneOne, DASA) and ClinVar contains an entry for this variant (Variation ID: 217882) - PS4; variant is located in a mutational hot spot and/or critical and well-established functional domain - PM1; this variant is not present in population databases (rs863225297 - gnomAD no frequency; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2; this variant has been observed to segregate in ten italian families (PMID: 22664156) - PP1_strong; 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; in silico analysis predicts this variant is probably damaging to the protein structure/function - PP3; In summary, the currently available evidence indicates that the variant is pathogenic. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsApr 15, 2021This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. 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 mutations 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 02, 2023Advanced 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217882). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 396 of the NOTCH3 protein (p.Ser396Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 22664156, 32277177; Invitae). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.79
D;D
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.74
T;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.0
M;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-3.7
D;.
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0060
D;.
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;.
Vest4
0.88
MutPred
0.51
Loss of disorder (P = 0.0971);.;
MVP
1.0
MPC
1.3
ClinPred
0.99
D
GERP RS
4.7
Varity_R
0.73
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs863225297; hg19: chr19-15300089; API