NM_000435.3(NOTCH3):c.1283G>A (p.Cys428Tyr) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 4, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000710988.2

Allele description [Variation Report for NM_000435.3(NOTCH3):c.1283G>A (p.Cys428Tyr)]

NM_000435.3(NOTCH3):c.1283G>A (p.Cys428Tyr)

Gene:

NOTCH3:notch receptor 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.12

Genomic location:

Preferred name:

NM_000435.3(NOTCH3):c.1283G>A (p.Cys428Tyr)

HGVS:

NC_000019.10:g.15189084C>T
NG_009819.1:g.16898G>A
NM_000435.3:c.1283G>AMANE SELECT
NP_000426.2:p.Cys428Tyr
NC_000019.9:g.15299895C>T
NM_000435.2:c.1283G>A

Protein change:

C428Y

Links:

dbSNP: rs1568360455

NCBI 1000 Genomes Browser:

rs1568360455

Molecular consequence:

NM_000435.3:c.1283G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000841304	Athena Diagnostics Inc	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Sep 12, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15364702, 15834039, 26467025
SCV004297935	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 4, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15834039, 16009764, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000841304

Athena Diagnostics Inc

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Sep 12, 2017)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004297935

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 4, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients.

Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M.

Brain. 2004 Nov;127(Pt 11):2533-9. Epub 2004 Sep 13.

PubMed [citation]

PMID:: 15364702

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

See all PubMed Citations (5)

Details of each submission

From Athena Diagnostics Inc, SCV000841304.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004297935.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant disrupts the p.Cys428 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15834039; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 585591). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 15834039, 16009764). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 428 of the NOTCH3 protein (p.Cys428Tyr). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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