rs1285584068

Positions:

Variant summary

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

The NM_000435.3(NOTCH3):c.3091C>T(p.Arg1031Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,423,552 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.10

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]

NOTCH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a domain EGF-like 26 (size 34) in uniprot entity NOTC3_HUMAN there are 5 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, 0.924

PP5

Variant 19-15180732-G-A is Pathogenic according to our data. Variant chr19-15180732-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 447827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15180732-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.3091C>T	p.Arg1031Cys	missense_variant	19/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5 linkuse as main transcript	c.2935C>T	p.Arg979Cys	missense_variant	18/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.3091C>T	p.Arg1031Cys	missense_variant	19/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.2932C>T	p.Arg978Cys	missense_variant	18/23	5		ENSP00000473138

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1423552

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

704652

show subpopulations

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:

0.00000183

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 14, 2020	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. Assessment of experimental evidence suggests this variant results in abnormal protein function. Study showed this variant rescued stroke susceptibility phenotype in young notch 3 knock-out mice, but failed to rescue older mice suggesting it might be an age-dependent hypomorphic variant (PMID: 21555590). 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	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2023	PP2, PP4, PM1, PM2, PS3, PS4 -

NOTCH3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2024

The NOTCH3 c.3091C>T variant is predicted to result in the amino acid substitution p.Arg1031Cys. This variant has been reported in individuals with CADASIL (Joutel et al. 1997. PubMed ID: 9388399; Wang et al. 2022. PubMed ID: 35401403; Uemura et al. 2022. PubMed ID: 36261288). This variant has not been reported in a large population database, indicating this variant is rare. Most CADASIL causing variants in the NOTCH3 gene result in the gain or loss of one or more cysteine residues in the extracellular domain of the protein, as seen in this patient. This patient’s variant alters a cysteine residue and is located in the extracellular EGF-like domain 26. Pathogenic variants in EGF-like domains 1-6 appear to be fully penetrant and are usually associated with the classical CADASIL phenotype. However, there is variability in disease severity. Pathogenic variants in EGF-like domains 7-34 have a much higher population frequency, and can predispose to a milder small-vessel disease, possibly even displaying incomplete or at least very late onset complete penetrance (OMIM #125310; Rutten et al. 2016. PubMed ID: 27844030; Rutten et al. 2019. PubMed ID: 30032161). This variant is interpreted as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Aug 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;T

Eigen

Benign

0.011

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.95

D;T

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.5

N;.

REVEL

Uncertain

0.63

Sift

Benign

0.21

T;.

Sift4G

Benign

0.11

T;T

Polyphen

0.92

P;.

Vest4

0.80

MutPred

0.88

Gain of glycosylation at P1026 (P = 0.1166);.;

MVP

1.0

MPC

1.3

ClinPred

0.77

GERP RS

3.1

Varity_R

0.42

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over