ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.6809C>T (p.Thr2270Met) (rs148716935)

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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 RCV000516212 SCV000614331 benign not specified 2017-06-28 criteria provided, single submitter clinical testing
Invitae RCV000981773 SCV001129774 likely benign not provided 2018-10-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001123434 SCV001282275 likely benign Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000981773 SCV001549881 uncertain significance not provided no assertion criteria provided clinical testing The NOTCH3 p.Thr2270Met variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs148716935) and ClinVar (classified as benign by Athena Diagnostics Inc). The variant was identified in control databases in 40 of 282300 chromosomes at a frequency of 0.0001417 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 24 of 10356 chromosomes (freq: 0.002317), African in 3 of 24838 chromosomes (freq: 0.000121), Latino in 3 of 35424 chromosomes (freq: 0.000085) and European (non-Finnish) in 10 of 128818 chromosomes (freq: 0.000078), but was not observed in the East Asian, European (Finnish), Other, or South Asian populations. The p.Thr2270 residue is conserved across mammals and other 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.

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