ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.6061G>A (p.Val2021Met) (rs199620476)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000996809 SCV001151738 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002510 SCV001160469 uncertain significance not specified 2019-04-10 criteria provided, single submitter clinical testing The NOTCH3 c.6061G>A; p.Val2021Met variant (rs199620476), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is found in the general population with an overall allele frequency of 0.02% (61/271496 alleles) in the Genome Aggregation Database. The valine at codon 2021 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, nearly all pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). The p.Val2021Met does not occur within this critical region and is thus inconsistent with the presumed mechanism of disease for NOTCH3 pathogenic variants. However, due to limited information, the clinical significance of the p.Val2021Met variant is uncertain at this time. References: Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.
Illumina Clinical Services Laboratory,Illumina RCV001125542 SCV001284627 likely benign Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy type 1 2018-01-13 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.
Athena Diagnostics Inc RCV000996809 SCV001475723 likely benign not provided 2019-10-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000996809 SCV001548779 uncertain significance not provided no assertion criteria provided clinical testing The NOTCH3 p.Val2021Met variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs199620476) and in control databases in 61 of 271496 chromosomes at a frequency of 0.000225 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 6 of 6940 chromosomes (freq: 0.000865), Latino in 15 of 34494 chromosomes (freq: 0.000435), European (non-Finnish) in 38 of 123660 chromosomes (freq: 0.000307) and African in 2 of 23620 chromosomes (freq: 0.000085), but not in the Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The p.Val2021 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (MaxEntScan, GeneSplicer, NNSPLICE, SpliceSiteFinder-like) predict a greater than 10% difference in splicing; this is not very predictive of 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.

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