NM_000435.3(NOTCH3):c.3206A>G (p.Tyr1069Cys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 27, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV002043152.6

Allele description [Variation Report for NM_000435.3(NOTCH3):c.3206A>G (p.Tyr1069Cys)]

NM_000435.3(NOTCH3):c.3206A>G (p.Tyr1069Cys)

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.3206A>G (p.Tyr1069Cys)

HGVS:

NC_000019.10:g.15180193T>C
NG_009819.1:g.25789A>G
NM_000435.2:c.3206A>G
NM_000435.3:c.3206A>GMANE SELECT
NP_000426.2:p.Tyr1069Cys
NC_000019.9:g.15291004T>C

Protein change:

Y1069C

Links:

dbSNP: rs1438064001

NCBI 1000 Genomes Browser:

rs1438064001

Molecular consequence:

NM_000435.3:c.3206A>G - 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
SCV002301030	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 28, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19174371, 28492532
SCV004229495	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jun 27, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19174371, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002301030

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 28, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004229495

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Jun 27, 2023)

unknown

clinical testing

PubMed (2)
[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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients.

Tikka S, Mykkänen K, Ruchoux MM, Bergholm R, Junna M, Pöyhönen M, Yki-Järvinen H, Joutel A, Viitanen M, Baumann M, Kalimo H.

Brain. 2009 Apr;132(Pt 4):933-9. doi: 10.1093/brain/awn364. Epub 2009 Jan 27.

PubMed [citation]

PMID:: 19174371
PMCID:: PMC2668941

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002301030.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1069 of the NOTCH3 protein (p.Tyr1069Cys). This missense change has been observed in individual(s) with CADASIL (PMID: 19174371). This variant is present in population databases (no rsID available, gnomAD 0.004%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 1510760).

#	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 Athena Diagnostics, SCV004229495.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with CADASIL. 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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine