ClinVar Miner

Submissions for variant NM_020774.4(MIB1):c.2827G>T (p.Val943Phe)

gnomAD frequency: 0.00013  dbSNP: rs200035428
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001091988 SCV001248313 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
GeneDx RCV001091988 SCV001801098 uncertain significance not provided 2024-07-22 criteria provided, single submitter clinical testing Identified in patients with LVNC or DCM in published literature ; several patients also harbored additional cardiogenetic variants (PMID: 23314057, 30847666, 33662488, 36325906); Published functional studies using a mouse model suggest that mice expressing the p.(V943F) allele develop biscupid aortic valve (BAV) in a NOTCH-sensitized genetic background and their embryonic myocardium displays LVNC features (PMID: 36325906); Published functional studies suggest reduced signaling (PMID: 23314057); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27285058, 27260948, 34426522, 33443154, 33662488, 31629663, 36325906, 23314057, 30847666)
PreventionGenetics, part of Exact Sciences RCV003390715 SCV004120059 uncertain significance MIB1-related disorder 2022-11-01 criteria provided, single submitter clinical testing The MIB1 c.2827G>T variant is predicted to result in the amino acid substitution p.Val943Phe. This variant has been reported to segregate in a three generation pedigree with six individuals with left ventricular noncompaction (Luxán et al. 2013. PubMed ID: 23314057). This variant was also reported in individuals with dilated cardiomyopathy (Supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666; Table S6, Alimohamed et al. 2021. PubMed ID: 33662488). However, this variant was also documented in one homozygous and eight heterozygous unrelated Turkish individuals with unknow phenotypes in a population-based study (Dataset S4, Kars et al. 2021. PubMed ID: 34426522). Functional studies indicate this variant results in a reduction of JAG1 ubiquitination when co-expressed with wild type MIB1 and injection of mRNA with this variant into zebrafish embryos may disrupt normal cardiac development (Luxán et al. 2013. PubMed ID: 23314057). This variant is reported in 0.054% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-19438554-G-T) and has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain to pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/40091). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
OMIM RCV000033169 SCV000056951 pathogenic Left ventricular noncompaction 7 2013-02-01 no assertion criteria provided literature only

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