rs1285584068

chr19-15180732-G-Achr19-15180732-G-Cchr19-15180732-G-T

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.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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.10

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 26 (size 34) in uniprot entity NOTC3_HUMAN there are 18 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	UniProt
NOTCH3	NM_000435.3	c.3091C>T	p.Arg1031Cys	missense_variant	19/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.2935C>T	p.Arg979Cys	missense_variant	18/32

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1423552 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 704652

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

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 -

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	D
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;T
Eigen	Benign	0.011
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.95	D;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.36	T
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	D
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

Other links and lift over

dbSNP: rs1285584068; hg19: chr19-15291543; COSMIC: COSV54628005; COSMIC: COSV54628005;