rs199638166

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_000435.3(NOTCH3):c.3664T>G(p.Cys1222Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7O:1

Conservation

PhyloP100: 8.67

Variant links:

Genes affected

NOTCH3 (HGNC:7883): (notch receptor 3) This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

NOTCH3 links:

MIR6795 (HGNC:50031): (microRNA 6795) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6795 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.3664T>G	p.Cys1222Gly	missense_variant	Exon 22 of 33	ENST00000263388.7	NP_000426.2	Q9UM47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 link	c.3664T>G	p.Cys1222Gly	missense_variant	Exon 22 of 33	1	NM_000435.3	ENSP00000263388.1		Q9UM47

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000958

AC:

AN:

250496

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000180

AC:

263

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

121

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000225

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000105

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:4

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOTCH3: PM1:Strong, PS4:Moderate -

Dec 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1222 of the NOTCH3 protein (p.Cys1222Gly). This variant is present in population databases (rs199638166, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with NOTCH3-related conditions or cognitively healthy elderly controls (PMID: 24840674, 26305465, 32573853, 32732295). ClinVar contains an entry for this variant (Variation ID: 425164). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. 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. -

Sep 17, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PM1, PM2 -

Oct 16, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) This variant is statistically significantly enriched in affected patients as compared to ethnically matched controls (PMID: 39271666). This variant has been seen where an alternate explanation for disease was also identified, suggesting this variant may not 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). -

Sep 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NOTCH3 c.3664T>G; p.Cys1222Gly variant (rs199638166, ClinVar Variation ID: 425164) is reported in the literature in several individuals and families with clinical features of CADASIL (Cho 2022, Juhosova 2023, Kilarski 2015, Moreton 2014, Ramirez 2020, Rutten 2020, Tan 2019). This variant was also found in a cognitively healthy 84-year-old control, with no history of stroke or other neurologic symptoms but did have subtle white matter hyperintensities (Rutten 2020). This variant is found in the non-Finnish European population with an allele frequency of 0.02% (28/128,560 alleles) in the Genome Aggregation Database (v2.1.1). Additionally, the p.Cys1222Gly variant was found in 212 Caucasian individuals in the UK biobank (Cho 2022). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.524). Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). However, due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Cho BPH et al. Association of Vascular Risk Factors and Genetic Factors With Penetrance of Variants Causing Monogenic Stroke. JAMA Neurol. 2022 Dec 1;79(12):1303-1311. PMID: 36300346. Juhosova M et al. Influence of different spectra of NOTCH3 variants on the clinical phenotype of CADASIL - experience from Slovakia. Neurogenetics. 2023 Jan;24(1):1-16. PMID: 36401683. Kilarski LL et al. Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke. PLoS One. 2015 Aug 25;10(8):e0136352. PMID: 26305465. Moreton FC et al. Changing clinical patterns and increasing prevalence in CADASIL. Acta Neurol Scand. 2014 Sep;130(3):197-203. PMID: 24840674. Ramirez J et al. Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities. Mov Disord. 2020 Nov;35(11):2090-2095. PMID: 32573853. Rutten JW et al. Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance. Neurology. 2020 Sep 29;95(13):e1835-e1843. PMID: 32732295. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. PMID: 24844136. Tan RYY et al. How common are single gene mutations as a cause for lacunar stroke? A targeted gene panel study. Neurology. 2019 Nov 26;93(22):e2007-e2020. PMID: 31719132. -

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Uncertain:2Other:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Both loss of function and dominant negative have been suggested as mechanisms in CADASIL (MIM#125310), however lateral meningocele syndrome (MIM#130720) results from a gain of function (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The p.(Arg544Cys) variant is associated with a later age of onset and milder clinical features than other NOTCH3 variants (GeneReviews, PMID: 26308724). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to glycine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (42 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant affects a cysteine residue involved in disulfide bonding (DECIPHER, PMID: 32732295). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported once as pathogenic, and more commonly as a VUS (ClinVar). It has been observed in at least three individuals with CADASIL (PMID: 24840674, PMID: 36401683), four individuals with Parkinsons disease or stroke (PMID: 26305465, PMID: 32573853, PMID: 31719132), and also in a healthy control with subtle white matter hyperintensities (PMID: 32732295). Lastly, this variant is highly prevalent in the UK Biobank cohort (PMID: 36300346). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

GenomeConnect - CureCADASIL

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 11-07-2016 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -

not specified

Uncertain:1

May 10, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

D;D

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

T;T

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

5.4

H;.

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-11

D;.

REVEL

Uncertain

0.52

Sift

Uncertain

0.0030

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.97

MVP

0.98

MPC

1.4

ClinPred

0.97

GERP RS

3.9

Varity_R

0.99

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over