ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.3853G>A (p.Val1285Met) (rs756972680)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519706 SCV000618910 uncertain significance not provided 2020-11-16 criteria provided, single submitter clinical testing Reported in one proband with hypoplastic left heart syndrome, though clinical and segregation details are not available (Helle et al., 2019); Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 450338; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25587027, 30511478)
Invitae RCV000693083 SCV000820938 uncertain significance Adams-Oliver syndrome 5 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1285 of the NOTCH1 protein (p.Val1285Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs756972680, ExAC 0.01%). This variant has not been reported in the literature in individuals with NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID:450338). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
University of Washington Center for Mendelian Genomics, University of Washington RCV001291516 SCV001480024 uncertain significance Hypoplastic left heart syndrome no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000519706 SCV001549993 uncertain significance not provided no assertion criteria provided clinical testing The NOTCH1 p.Val1285Met variant was identified in 1/49 probands with hypoplastic left heart syndrome (Helle_2017_PMID:30511478) and 1/108 B-chronic lymphocytic leukemia patients (Athanasakis_2014_PMID:25587027). The variant was identified in dbSNP (ID: rs756972680), ClinVar (classified as uncertain significance by GeneDx and Invitae for Adams-Oliver Syndrome 5) and LOVD 3.0 (classified as uncertain significance by VKGL-NL). The variant was identified in control databases in 14 of 267496 chromosomes at a frequency of 0.00005234 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 3 of 6838 chromosomes (freq: 0.000439), European (non-Finnish) in 9 of 121848 chromosomes (freq: 0.000074), South Asian in 1 of 29434 chromosomes (freq: 0.000034) and Latino in 1 of 34386 chromosomes (freq: 0.000029), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Val1285 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 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000519706 SCV001929963 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000519706 SCV001953549 uncertain significance not provided no assertion criteria provided clinical testing

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