Submissions for variant NM_000435.3(NOTCH3):c.3691C>T (p.Arg1231Cys)

gnomAD frequency: 0.00089  dbSNP: rs201680145

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UCLA Clinical Genomics Center, UCLA	RCV000200615	SCV000255424	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2014-05-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000710090	SCV000513946	uncertain significance	not provided	2016-08-30	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics	RCV000710090	SCV000614291	uncertain significance	not provided	2024-04-03	criteria provided, single submitter	clinical testing	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 individuals with CADASIL than in the general population and/or healthy controls. This variant segregates with CADASIL in at least one family. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Computational tools predict that this variant is damaging. 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).
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000200615	SCV000746512	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2017-12-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000710090	SCV001018608	uncertain significance	not provided	2024-10-01	criteria provided, single submitter	clinical testing	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%), and has an allele count higher than expected for a pathogenic variant. 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, 30212743, 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Mendelics	RCV000200615	SCV001141023	uncertain significance	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000710090	SCV001474050	uncertain significance	not provided	2021-10-20	criteria provided, single submitter	clinical testing	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.
MGZ Medical Genetics Center	RCV000200615	SCV002579125	uncertain significance	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2022-04-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710090	SCV002822534	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	NOTCH3: PP2, BS1, BS2
Mayo Clinic Laboratories, Mayo Clinic	RCV000710090	SCV004224578	uncertain significance	not provided	2022-11-08	criteria provided, single submitter	clinical testing	PP2, PP4, PM1
Revvity Omics, Revvity	RCV000710090	SCV004235620	uncertain significance	not provided	2023-11-20	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000200615	SCV005373644	pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.3691C>T(p.Arg1231Cys) in NOTCH3 gene has been reported previously in homozygous and heterozygous state in multiple individuals with CADASIL (Abou Al-Shaar et al., 2016, Rinnoci et al., 2013). The c.3691C>T variant 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 et al, 2016). 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. This variant has been reported to the ClinVar database with varying interpretations as Likely Benign/ Uncetain Significance/ Pathogenic. Multiple lines of computational evidence (SIFT - damaging; Polyphen - possibly damaging; Mutation Taster - disease causing) predict a damaging effect on protein structure and function for this variant. TThe amino acid Arginine at position 1231 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Arg1231Cys in NOTCH3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000710090	SCV001549443	uncertain significance	not provided		no assertion criteria provided	clinical testing	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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000710090	SCV002036564	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000710090	SCV002037699	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737316	SCV005351341	likely pathogenic	NOTCH3-related disorder	2024-03-27	no assertion criteria provided	clinical testing	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.