19-15197503-C-T

Variant names:

• chr19-15197503-C-T
• NM_000435.3:c.194G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000435.3(NOTCH3):​c.194G>A​(p.Cys65Tyr) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.59

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 16 ACMG points.

• PM1: In a domain EGF-like 1 (size 37) in uniprot entity NOTC3_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_000435.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 19-15197503-C-T is Pathogenic according to our data. Variant chr19-15197503-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1365706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15197503-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.194G>A	p.Cys65Tyr	missense_variant	Exon 2 of 33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.194G>A	p.Cys65Tyr	missense_variant	Exon 2 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.194G>A	p.Cys65Tyr	missense_variant	Exon 2 of 33	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000601011.1	c.191G>A	p.Cys64Tyr	missense_variant	Exon 2 of 23	5		ENSP00000473138.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Apr 01, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in at least one individual with clinical features of CADASIL. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of pathogenic variants identified in NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain. -

Mar 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH3 protein function. This variant disrupts the p.Cys65 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15364702, 16009764, 21078731). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1365706). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 65 of the NOTCH3 protein (p.Cys65Tyr). 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 (CADASIL) (PMID: 23025651; Invitae). -

Feb 19, 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.194G>A; p.Cys65Tyr variant (rs1555730176) is reported in the literature in several individuals affected with CADASIL (Kim 2020, Lackovic 2012, Mukai 2020, Rufa 2007). This variant is reported in ClinVar (Variation ID: 1365706). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.876). Additionally, another variant at this codon (c.194G>C; p.Cys65Ser) has been reported in individuals with CADASIL (Mukai 2020, Opherk 2004). Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), and thus the p.Cys65Tyr variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Kim H et al. Clinical and imaging features of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and cysteine-sparing NOTCH3 mutations. PLoS One. 2020 Jun 18;15(6):e0234797. PMID: 32555735. Lackovic V et al. Skin and sural nerve biopsies: ultrastructural findings in the first genetically confirmed cases of CADASIL in Serbia. Ultrastruct Pathol. 2012 Oct;36(5):325-35. PMID: 23025651. 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. Opherk C et al. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004 Nov;127(Pt 11):2533-9. PMID: 15364702. Rufa A et al. Cardiac autonomic nervous system and risk of arrhythmias in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Stroke. 2007 Feb;38(2):276-80. PMID: 17218610. 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. -

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

Dec 03, 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.194G>A (p.Cys65Tyr) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 243168 control chromosomes. c.194G>A has been reported in the literature in individuals affected with Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25344745, 35641310, 32277177). ClinVar contains an entry for this variant (Variation ID: 1365706). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 01, 2022

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NOTCH3-related disorder Pathogenic:1

Feb 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NOTCH3 c.194G>A variant is predicted to result in the amino acid substitution p.Cys65Tyr. This variant was reported in individuals with CADASIL (Lackovic et al. 2012. PubMed ID: 23025651; Mukai et al. 2020. PubMed ID: 32277177). 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 one. 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 (OMIM #125310; Rutten et al. 2016. PubMed ID: 27844030; Rutten et al. 2019. PubMed ID: 30032161). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-9.0	D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		1.0		Gain of phosphorylation at C65 (P = 0.0514);.;
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.99
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-15308314;