rs863225297

Positions:

• chr19-15189278-G-C

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.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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.58

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 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
NOTCH3	NM_000435.3	c.1187C>G	p.Ser396Cys	missense_variant	7/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.1187C>G	p.Ser396Cys	missense_variant	7/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.1187C>G	p.Ser396Cys	missense_variant	7/33	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000601011.1	c.1184C>G	p.Ser395Cys	missense_variant	7/23	5		ENSP00000473138.1

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

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Mendelics	Jul 25, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Sep 02, 2021	The 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 submitter	clinical testing	Athena Diagnostics	Apr 15, 2021	This 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 submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 02, 2023	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. 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

Other links and lift over

dbSNP: rs863225297; hg19: chr19-15300089;