rs201680145

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000435.3(NOTCH3):c.3691C>T(p.Arg1231Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000478 in 1,614,208 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00050 ( 3 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:10B:1

Conservation

PhyloP100: 4.97

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02636671).

BS2

High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.3691C>T	p.Arg1231Cys	missense_variant	22/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5 linkuse as main transcript	c.3535C>T	p.Arg1179Cys	missense_variant	21/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.3691C>T	p.Arg1231Cys	missense_variant	22/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.3532C>T	p.Arg1178Cys	missense_variant	21/23	5		ENSP00000473138
NOTCH3	ENST00000595045.1 linkuse as main transcript	n.527C>T		non_coding_transcript_exon_variant	2/3	2
NOTCH3	ENST00000600841.1 linkuse as main transcript	n.169C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.000236

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000887

AC:

222

AN:

250384

Hom.:

AF XY:

0.00112

AC XY:

152

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000637

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00536

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000274

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000504

AC:

737

AN:

1461846

Hom.:

Cov.:

AF XY:

0.000649

AC XY:

472

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00494

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000194

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.000230

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000232

Hom.:

Bravo

AF:

0.000204

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000988

AC:

120

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:7Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 22, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. 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). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NOTCH3: PP2, BS1, BS2 -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NOTCH3 p.(Arg1231Cys) variant was identified in 3 of 206 proband chromosomes (frequency: 0.015) from individuals or families with Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or a strong suspicion of CADASIL and was not identified in 200 control chromosomes from healthy individuals (Testi_2012_PMID: 22664156; Joutel_1997_PMID: 9388399). The variant was also identified in dbSNP (ID: rs201680145), Clinvitae, Cosmic, MutDB, LOVD 3.0 and ClinVar (reported as pathogenic for CADASIL by UCLA Clinical Genomics Center and Genomic Research Center, Shahid Beheshti University of Medical Sciences however reported as a VUS by GeneDX and Athena Diagnostics Inc). The variant was identified in control databases in 225 of 281770 chromosomes (3 homozygous) at a frequency of 0.000799 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 164 of 30614 chromosomes (freq: 0.005357), Latino in 22 of 35400 chromosomes (freq: 0.000622), Other in 4 of 7200 chromosomes (freq: 0.000556), European (non-Finnish) in 34 of 128480 chromosomes (freq: 0.000265) and East Asian in 1 of 19924 chromosomes (freq: 0.00005), while the variant was not observed in the African, Ashkenazi Jewish, and European (Finnish) populations. The R1231C variant was recently identified in the homozygous state in several members from a large family with CADASIL (Abou Al-Shaar_2016_PMID: 27423596). These homozygous individuals had phenotypic features that were within the spectrum of CADASIL, though on the slightly severe end compared to their affected family members with R1231C in the heterozygous state (Abou Al-Shaar_2016_ PMID: 27423596). The R1231C variant was also identified in a 55 year old patient with a sudden depressive episode as well as loss of ability to execute or carry out learned purposeful movements, expressive aphasia, and mild alterations in some cognitive domains such as attention and executive functions (Ungaro_2009_ PMID: 19259619). Valenti et al. (2008) reported an Italian patient with the Arg1231Cys mutation affected by CADASIL as well as a depressive episode at the age of 50 (Valenti_2008_PMID: 18384453). The p.Arg1231 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 08, 2022	PP2, PP4, PM1 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2021	The NOTCH3 c.3691C>T; p.Arg1231Cys variant (rs201680145), is reported in the literature in individuals with CADASIL (Abou Al-Shaar 2016, Joutel 1997, Rinnoci 2013), and in an individual with Alzheimer's disease but no features of CADASIL (Guerreiro 2012). In one family affected with CADASIL, seven family members were found to be homozygous for the variant and had a slightly more severe phenotype than the six family members heterozygous for the variant (Abou Al-Shaar 2016). The p.Arg1231Cys variant is also reported in the ClinVar database (Variation ID: 216972). It is found in the general population with an overall allele frequency of 0.08% (225/281770 alleles, including 3 homozygotes), with an increased frequency of 0.5% in the South Asian population (Genome Aggregation Database). The arginine at codon 1231 is located in an EGF-like domain; 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, given the high frequency of this variant in the general population, and asymptomatic heterozygous carriers that have been reported, the clinical significance of this variant is uncertain at this time. References: Abou Al-Shaar H et al. Phenotypic comparison of individuals with homozygous or heterozygous mutation of NOTCH3 in a large CADASIL family. J Neurol Sci. 2016 Aug 15;367:239-43. Guerreiro RJ et al. Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease. Neurobiol Aging. 2012 May;33(5):1008.e17-23. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Rinnoci V et al. Cerebral hemorrhages in CADASIL: report of four cases and a brief review. J Neurol Sci. 2013 Jul 15;330(1-2):45-51. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1231 of the NOTCH3 protein (p.Arg1231Cys). This variant is present in population databases (rs201680145, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 9388399, 12395806, 15229130, 19006080, 22664156, 23639391, 25326637, 31915071, 32128266, 33013620, 33712516). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 216972). 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 with a positive predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2016	The R1231C variant in the NOTCH3 gene has been reported previously in association with CADASIL (Joutel et al., 1997; Rinnoci et al., 2013; Abou Al-Shaar et al., 2016). The R1231C variant was recently identified in the homozygous state in several members from a large family with CADASIL (Abou Al-Shaar et al., 2016). These homozygous individuals had phenotypic features that were within the spectrum of CADASIL, though on the slightly severe end compared to their affected family members with R1231C in the heterozygous state (Abou Al-Shaar et al., 2016). The R1231C variant was also identified by whole exome sequencing in an individual with Alzheimer's disease and no features of CADASIL, which the authors conclude either leads to questions of the pathogenicity of R1231C or broadens the phenotypic spectrum associated with this variant (Guerreiro et al., 2012). The R1231C 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. While this substitution occurs at a position that is not conserved across species, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R1231C variant was observed in 0.58% of alleles from individuals of South Asian background, including three homozygous individuals, in the Exome Aggregation Consortium (ExAC) data set, indicating it may be a rare benign variant in this population. We have also identified many unaffected individuals who are heterozygous for the R1231C variant at GeneDx. As the R1231C variant is observed with significant frequency among unaffected individuals in the ExAC data set and at GeneDx, we now interpret R1231C as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 20, 2023	- -

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

Pathogenic:2Uncertain:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	May 27, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	- -

NOTCH3-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2024

The NOTCH3 c.3691C>T variant is predicted to result in the amino acid substitution p.Arg1231Cys. This variant has been reported in numerous individuals affected with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Joutel et al. 1997. PubMed ID: 9388399; Bianchi et al. 2015. PubMed ID: 25344745). However, this variant has also been documented in the gnomAD database with a subpopulation allele frequency up to 0.5%, including presence in two homozygous individuals. This carrier frequency is higher than the expected prevalence of CADASIL. The data for this variant support an association with CADASIL that is predicted to be fully penetrant, but milder and later onset than typical CADASIL (Rutten et al. 2016. PubMed ID: 27844030). Of interest, rare patients with this variant in the homozygous or compound heterozygous states present in the age range and phenotypic severity of typical CADASIL (Abou Al-Shaar. 2016. PubMed ID: 27423596; Abramycheva et al. 2015. PubMed ID: 25623805). In summary, we interpret this variant as likely pathogenic for late-onset CADASIL. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;D

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.48

T;T

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.026

T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Pathogenic

3.4

M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-4.7

D;.

REVEL

Pathogenic

0.70

Sift

Benign

0.074

T;.

Sift4G

Uncertain

0.012

D;D

Polyphen

0.84

P;.

Vest4

0.80

MVP

0.88

MPC

1.2

ClinPred

0.16

GERP RS

3.9

Varity_R

0.43

gMVP

0.58

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