NM_000435.3(NOTCH3):c.505C>T (p.Arg169Cys) AND NOTCH3-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 23, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004532317.4

Allele description [Variation Report for NM_000435.3(NOTCH3):c.505C>T (p.Arg169Cys)]

NM_000435.3(NOTCH3):c.505C>T (p.Arg169Cys)

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.505C>T (p.Arg169Cys)

HGVS:

NC_000019.10:g.15192134G>A
NG_009819.1:g.13848C>T
NM_000435.3:c.505C>TMANE SELECT
NP_000426.2:p.Arg169Cys
NC_000019.9:g.15302945G>A
NM_000435.2:c.505C>T
Q9UM47:p.Arg169Cys

Protein change:

R169C; ARG169CYS

Links:

UniProtKB: Q9UM47#VAR_012880; OMIM: 600276.0002; dbSNP: rs28933696

NCBI 1000 Genomes Browser:

rs28933696

Molecular consequence:

NM_000435.3:c.505C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: NOTCH3-related disorder
Synonyms:: NOTCH3-Related Disorders; NOTCH3-related condition
Identifiers:

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Mus musculus testis derived transcript, mRNA (cDNA clone MGC:6093 IMAGE:3589585)...
Mus musculus testis derived transcript, mRNA (cDNA clone MGC:6093 IMAGE:3589585), complete cds
gi|13277857|gb|BC003808.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004120649	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (Jul 1, 2024)	germline	clinical testing
SCV005202928	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 23, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32277177, 12754354, 21940951 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004120649

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(Jul 1, 2024)

germline

clinical testing

SCV005202928

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 23, 2024)

germline

clinical testing

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

Citation Link

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

Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients.

Mukai M, Mizuta I, Watanabe-Hosomi A, Koizumi T, Matsuura J, Hamano A, Tomimoto H, Mizuno T.

J Hum Genet. 2020 Aug;65(8):637-646. doi: 10.1038/s10038-020-0751-9. Epub 2020 Apr 10.

PubMed [citation]

PMID:: 32277177

Coexistence of CADASIL and Alzheimer's disease.

Thijs V, Robberecht W, De Vos R, Sciot R.

J Neurol Neurosurg Psychiatry. 2003 Jun;74(6):790-2.

PubMed [citation]

PMID:: 12754354
PMCID:: PMC1738501

See all PubMed Citations (3)

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004120649.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The NOTCH3 c.505C>T variant is predicted to result in the amino acid substitution p.Arg169Cys. This variant has been observed in numerous patients with CADASIL and is located in a mutation hotspot (Ni et al. 2022. PubMed ID: 35822697). Its pathogenicity is supported by functional studies (Lynch et al. 2017. PubMed ID: 28334938; Wallays et al. 2011. PubMed ID: 21940951). 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 adds a cysteine residue and is located in the extracellular EGF-like domain 4. 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.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005202928.1

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

Description

Variant summary: NOTCH3 c.505C>T (p.Arg169Cys) results in a non-conservative amino acid change in 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 247840 control chromosomes. c.505C>T has been reported in the literature in multiple individuals affected with NOTCH3-Related Disorders (example, Thijs_2003, Mukai_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence, which suggests this variant may affect protein function in a knock-in mouse model (Wallays_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21940951, 32277177, 12754354). ClinVar contains an entry for this variant (Variation ID: 9219). Based on the evidence outlined above, the variant was 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: Oct 13, 2024

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