NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys) AND not provided

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Mar 5, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000517748.5

Allele description [Variation Report for NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)]

NM_000435.3(NOTCH3):c.619C>T (p.Arg207Cys)

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.619C>T (p.Arg207Cys)
HGVS:
  • NC_000019.10:g.15192020G>A
  • NG_009819.1:g.13962C>T
  • NM_000435.3:c.619C>TMANE SELECT
  • NP_000426.2:p.Arg207Cys
  • NC_000019.9:g.15302831G>A
  • NM_000435.2:c.619C>T
Protein change:
R207C
Links:
dbSNP: rs775267348
NCBI 1000 Genomes Browser:
rs775267348
Molecular consequence:
  • NM_000435.3:c.619C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000614321Athena Diagnostics Inccriteria provided, single submitter
Pathogenic
(Mar 5, 2019)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000617300GeneDxcriteria provided, single submitter
Likely pathogenic
(Oct 5, 2017)
germlineclinical testing

Citation Link,

SCV001249853CeGaT Praxis fuer Humangenetik Tuebingencriteria provided, single submitter
Pathogenic
(Jan 1, 2019)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL).

Abramycheva N, Stepanova M, Kalashnikova L, Zakharova M, Maximova M, Tanashyan M, Lagoda O, Fedotova E, Klyushnikov S, Konovalov R, Sakharova A, Illarioshkin S.

J Neurol Sci. 2015 Feb 15;349(1-2):196-201. doi: 10.1016/j.jns.2015.01.018. Epub 2015 Jan 17.

PubMed [citation]
PMID:
25623805

Genotype-phenotype correlations of cysteine replacement in CADASIL.

Matsushima T, Conedera S, Tanaka R, Li Y, Yoshino H, Funayama M, Ikeda A, Hosaka Y, Okuzumi A, Shimada Y, Yamashiro K, Motoi Y, Nishioka K, Hattori N.

Neurobiol Aging. 2017 Feb;50:169.e7-169.e14. doi: 10.1016/j.neurobiolaging.2016.10.026. Epub 2016 Nov 2.

PubMed [citation]
PMID:
27890607
See all PubMed Citations (7)

Details of each submission

From Athena Diagnostics Inc, SCV000614321.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The variant disrupts a cysteine residue in an EGF-like repeat domain, which are important for the structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV000617300.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The R207C variant in the NOTCH3 gene has been reported previously in 2 unrelated individuals with clinical features of CADASIL (Escary et al., 2000; Matsushima et al., 2017). The R207C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R207C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved, however this variant is located within the EGF-like 5 domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R207C as a likely pathogenic variant.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From CeGaT Praxis fuer Humangenetik Tuebingen, SCV001249853.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Nov 27, 2021

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