NM_000435.3(NOTCH3):c.160C>T (p.Arg54Cys) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 18, 2025
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:: RCV000516423.7

Allele description [Variation Report for NM_000435.3(NOTCH3):c.160C>T (p.Arg54Cys)]

NM_000435.3(NOTCH3):c.160C>T (p.Arg54Cys)

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.160C>T (p.Arg54Cys)

HGVS:

NC_000019.10:g.15197537G>A
NG_009819.1:g.8445C>T
NM_000435.3:c.160C>TMANE SELECT
NP_000426.2:p.Arg54Cys
NC_000019.9:g.15308348G>A
NM_000435.2:c.160C>T

Protein change:

R54C

Links:

dbSNP: rs1555730189

Molecular consequence:

NM_000435.3:c.160C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000614231	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	pathogenic (Aug 19, 2025)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 19242647, 19006080, 38713890, 37458844, 38520151, 26270344, 26368811, 24139282, 32277177, 26002683, 11102981, 26467025
SCV005838821	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 10, 2025)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19006080, 19242647, 26270344, 32277177, 28492532
SCV007136965	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 18, 2025)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 11102981, 21616505, 22664156, 26002683, 26270344, 32102741, 32277177, 32555735, 34758253, 36047879, 36380532, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000614231

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

pathogenic
(Aug 19, 2025)

unknown

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV005838821

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 10, 2025)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV007136965

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 18, 2025)

germline

clinical testing

PubMed (12)
[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

Association of NOTCH3 Variant Risk Category With 2-Year Clinical and Radiologic Small Vessel Disease Progression in Patients With CADASIL.

Cerfontaine MN, Hack RJ, Gesierich B, Duering M, Witjes-Ané MW, Rodríguez-Girondo M, Gravesteijn G, Rutten J, Lesnik Oberstein SAJ.

Neurology. 2024 May 28;102(10):e209310. doi: 10.1212/WNL.0000000000209310. Epub 2024 May 7.

PubMed [citation]

PMID:: 38713890
PMCID:: PMC11177591

Acute bilateral multiple subcortical infarcts as manifestation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Huang H, Xie W, Hu F, Lv H, Wu Y, Cai B.

Neurol Sci. 2023 Dec;44(12):4391-4399. doi: 10.1007/s10072-023-06949-9. Epub 2023 Jul 17.

PubMed [citation]

PMID:: 37458844

See all PubMed Citations (21)

Details of each submission

From Athena Diagnostics, SCV000614231.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features of CADASIL. This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV005838821.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 54 of the NOTCH3 protein (p.Arg54Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 19006080, 19242647, 26270344, 32277177). ClinVar contains an entry for this variant (Variation ID: 447791). 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) indicates that this missense variant is expected to disrupt NOTCH3 protein function with a positive predictive value of 95%. 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

From Mayo Clinic Laboratories, Mayo Clinic, SCV007136965.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (12)

Description

PP1, PP2, PP3, PP4, PM1, PM2_supporting, PS4

#	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: Apr 12, 2026

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