NM_000435.3(NOTCH3):c.6061G>A (p.Val2021Met) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Oct 15, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000996809.3

Allele description [Variation Report for NM_000435.3(NOTCH3):c.6061G>A (p.Val2021Met)]

NM_000435.3(NOTCH3):c.6061G>A (p.Val2021Met)

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.6061G>A (p.Val2021Met)
HGVS:
  • NC_000019.10:g.15161567C>T
  • NG_009819.1:g.44415G>A
  • NM_000435.3:c.6061G>AMANE SELECT
  • NP_000426.2:p.Val2021Met
  • NC_000019.9:g.15272378C>T
  • NM_000435.2:c.6061G>A
Protein change:
V2021M
Links:
dbSNP: rs199620476
NCBI 1000 Genomes Browser:
rs199620476
Molecular consequence:
  • NM_000435.3:c.6061G>A - 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
SCV001151738CeGaT Praxis fuer Humangenetik Tuebingencriteria provided, single submitter
Uncertain significance
(Jan 1, 2019)
germlineclinical testing

Citation Link,

SCV001475723Athena Diagnostics Inccriteria provided, single submitter
Likely benign
(Oct 15, 2019)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001548779Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedUncertain significanceunknownclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes1not providednot providednot providednot providedclinical 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

Details of each submission

From CeGaT Praxis fuer Humangenetik Tuebingen, SCV001151738.6

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

From Athena Diagnostics Inc, SCV001475723.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001548779.1

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

Description

The NOTCH3 p.Val2021Met variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs199620476) and in control databases in 61 of 271496 chromosomes at a frequency of 0.000225 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 6 of 6940 chromosomes (freq: 0.000865), Latino in 15 of 34494 chromosomes (freq: 0.000435), European (non-Finnish) in 38 of 123660 chromosomes (freq: 0.000307) and African in 2 of 23620 chromosomes (freq: 0.000085), but not in the Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The p.Val2021 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (MaxEntScan, GeneSplicer, NNSPLICE, SpliceSiteFinder-like) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

Last Updated: Jul 10, 2021

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