ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.3691C>T (p.Arg1231Cys) (rs201680145)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000200615 SCV000255424 pathogenic Cerebral autosomal dominant arteriopathy 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 Inc RCV000710090 SCV000614291 uncertain significance not provided 2020-10-28 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000200615 SCV000746512 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2017-12-03 criteria provided, single submitter clinical testing
Invitae RCV000710090 SCV001018608 benign not provided 2018-01-09 criteria provided, single submitter clinical testing
Mendelics RCV000200615 SCV001141023 uncertain significance Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287366 SCV001474050 uncertain significance none provided 2019-12-12 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.
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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.