19-15180761-T-C

Variant names:

• chr19-15180761-T-C
• rs1167405466
• NM_000435.3:c.3062A>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000435.3(NOTCH3):​c.3062A>G​(p.Tyr1021Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,138 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 Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: -0.196
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• lateral meningocele syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• infantile myofibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myofibromatosis, infantile, 2

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000435.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754
• PP5: Variant 19-15180761-T-C is Pathogenic according to our data. Variant chr19-15180761-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 447825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.3062A>G	p.Tyr1021Cys	missense_variant	Exon 19 of 33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.2906A>G	p.Tyr969Cys	missense_variant	Exon 18 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.3062A>G	p.Tyr1021Cys	missense_variant	Exon 19 of 33	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000601011.1	c.2903A>G	p.Tyr968Cys	missense_variant	Exon 18 of 23	5		ENSP00000473138.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000229 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Feb 23, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP4, PM1, PS4

Dec 20, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in the heterozygous state in individuals with clinical features of CADASIL (PMID: 12146805, 18803652, 20038773, 32765252, 31998484, 34335700, 35775048; Ivan Tourtourikov et al., 2021); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37873835, 22878905, 15995828, 18803652, 20038773, 22367627, 21786151, 32765252, 32912545, 35754959, 34335700, 31998484, Ivan2021[Article], 37476306, Uemura_2022, 35775048, 30956055, 32277177, 12146805, 24844136, 36261288)

Feb 02, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features of CADASIL. This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. 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).

Sep 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NOTCH3 c.3062A>G; p.Tyr1021Cys variant (rs1167405466) is reported in the literature in several individuals affected with CADASIL (Hu 2021, Kalimo 2002, Mukai 2020, Pantoni 2010, Piccirillo 2008, Shindo 2020, Taniguchi 2022, Ueda 2022, Uppal 2019, Valenti 2012). This variant is also reported in ClinVar (Variation ID: 447825). It is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.658). However, this variant occurs in an EGF-like domain, and most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). Based on available information, this variant is considered to be likely pathogenic. References: Hu Y et al. NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients. Front Genet. 2021 Jul 15;12:705284. PMID: 34335700. Kalimo H et al. CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol. 2002 Jul;12(3):371-84. PMID: 12146805. Mukai M et al. Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients. J Hum Genet. 2020 Aug;65(8):637-646. PMID: 32277177. Pantoni L et al. Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients. Neurology. 2010 Jan 5;74(1):57-63. PMID: 20038773. Piccirillo G et al. Increased QT variability in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Eur J Neurol. 2008 Nov;15(11):1216-21. PMID: 18803652. 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. Shindo A et al. A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan. Front Aging Neurosci. 2020 Jul 14;12:216. PMID: 32765252. Taniguchi A et al. Imaging Characteristics for Predicting Cognitive Impairment in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy. Front Aging Neurosci. 2022 Jun 10;14:876437. PMID: 35754959. Ueda A et al. Detection of Vascular Notch3 Deposits in Unfixed Frozen Skin Biopsy Sample in CADASIL. Front Neurol. 2022 Jun 14;13:881528. PMID: 35775048. Uppal M et al. CADASIL presenting as late-onset mania with anosognosia. Clin Case Rep. 2019 Dec 8;8(1):47-50. PMID: 31998484. Valenti R et al. High lipoprotein(a) serum levels in three CADASIL families. J Neurol. 2012 Feb;259(2):379-80. PMID: 21786151.

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1021 of the NOTCH3 protein (p.Tyr1021Cys). 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: 18803652, 21786151, 31998484, 32277177). ClinVar contains an entry for this variant (Variation ID: 447825). Invitae Evidence 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 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.

Mar 17, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOTCH3-related disorder Pathogenic:2

Apr 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NOTCH3 c.3062A>G variant is predicted to result in the amino acid substitution p.Tyr1021Cys. This variant has been reported to be causative for CADASIL in several unrelated individuals (Kalimo et al. 2002. PubMed ID: 12146805; Pantoni et al. 2010. PubMed ID: 20038773). Of note, the vast majority of CADASIL-causing missense variants in the NOTCH3 gene result in the gain or loss of cysteine residues in the extracellular domain of the protein, as seen in this patient. This patient’s variant adds a cysteine residue and is located in the extracellular EGF-like domain 26. Pathogenic variants in EGF 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 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). At PreventionGenetics, we have previously identified this variant in other affected individuals. Taken together, we interpret this variant as pathogenic.

Sep 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NOTCH3 c.3062A>G (p.Tyr1021Cys) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 228302 control chromosomes (gnomAD). c.3062A>G has been reported in the literature in multiple individuals affected with CADASIL or related conditions (e.g. Kalimo_2002, Mukai_2020, Uppal_2020, Hu_2021, Uemura_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12146805, 32277177, 31998484, 34335700, 36261288). ClinVar contains an entry for this variant (Variation ID: 447825). Based on the evidence outlined above, the variant was classified as pathogenic.

Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Other:1

GenomeConnect - CureCADASIL

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Likely pathogenic and reported on 10-06-2017 by lab or GTR ID Fulgent. GenomeConnect - CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.3	L;.
PhyloP100		-0.20
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N;.
REVEL	Pathogenic	0.66
Sift	Benign	0.14	T;.
Sift4G	Benign	0.16	T;T
Vest4		0.83
ClinPred		0.29	T
GERP RS		3.0
Varity_R		0.41
gMVP		0.72
Mutation Taster		=90/10	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1167405466; hg19: chr19-15291572;