ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000710090 SCV000614291 uncertain significance not provided 2018-07-26 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.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000200615 SCV000746512 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy 2017-12-03 criteria provided, single submitter clinical testing
UCLA Clinical Genomics Center, UCLA RCV000200615 SCV000255424 pathogenic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy 2014-05-27 criteria provided, single submitter clinical testing

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