NM_000435.3(NOTCH3):c.580T>A (p.Cys194Ser) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 28, 2023
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:: RCV000711008.6

Allele description [Variation Report for NM_000435.3(NOTCH3):c.580T>A (p.Cys194Ser)]

NM_000435.3(NOTCH3):c.580T>A (p.Cys194Ser)

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.580T>A (p.Cys194Ser)

Other names:

p.Cys194Ser

HGVS:

NC_000019.10:g.15192059A>T
NG_009819.1:g.13923T>A
NM_000435.3:c.580T>AMANE SELECT
NP_000426.2:p.Cys194Ser
NC_000019.9:g.15302870A>T
NM_000435.2:c.580T>A

Protein change:

C194S

Links:

dbSNP: rs1568361818

NCBI 1000 Genomes Browser:

rs1568361818

Molecular consequence:

NM_000435.3:c.580T>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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rps15 [Zea perennis]
rps15 [Zea perennis]
Gene ID:27964187

Gene
ndhI [Zea perennis]
ndhI [Zea perennis]
Gene ID:27964184

Gene
ndhH [Zea perennis]
ndhH [Zea perennis]
Gene ID:27964186

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000841324	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jun 28, 2023)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29980472, 24840674, 15229130, 26467025
SCV004225183	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 29, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15229130, 20167921, 24840674, 28710804, 29370179, 29980472, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000841324

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Jun 28, 2023)

unknown

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004225183

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 29, 2022)

germline

clinical testing

PubMed (7)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

The influence of genetic and cardiovascular risk factors on the CADASIL phenotype.

Singhal S, Bevan S, Barrick T, Rich P, Markus HS.

Brain. 2004 Sep;127(Pt 9):2031-8. Epub 2004 Jun 30.

PubMed [citation]

PMID:: 15229130

See all PubMed Citations (8)

Details of each submission

From Athena Diagnostics, SCV000841324.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant has been identified in at least one individual with clinical features associated with 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 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).

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV004225183.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

PP3, PM1, PM2, PS1, PS4_moderate

#	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		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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