Submissions for variant NM_020774.4(MIB1):c.1588C>T (p.Arg530Ter)

gnomAD frequency: 0.00007  dbSNP: rs201850378

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485600	SCV000568835	uncertain significance	not provided	2017-12-06	criteria provided, single submitter	clinical testing	The R530X variant of uncertain significance in the MIB1 gene has been previously reported in one Southern European individual diagnosed with LVNC and was shown to segregate with disease in five additional affected relatives (Luxán et al., 2013). Using blood samples from affected relatives harboring R530X, Luxán et al. (2013) demonstrated that mutant mRNA expression is almost completely abolished and truncated MIB1 protein is not detectable, suggesting that R530X causes loss of protein expression through nonsense-mediated mRNA decay. Blood samples from these affected carriers also showed reduced NOTCH1 activity and target-gene expression (Luxán et al., 2013). In addition, the R530X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Nevertheless, only four other variants in the MIB1 gene have been reported in HGMD in association with MIB1-related disorders, and no other truncating variants in the MIB1 gene have been reported in association with cardiomyopathy (Stenson et al., 2014). Thus, the mechanism of disease for variants in the MIB1 gene remains to be definitely established. Identification of the R530X variant in additional affected individuals, larger segregation studies, and further functional evidence are necessary to further clarify the role of this variant in disease.Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000033170	SCV000743478	likely pathogenic	Left ventricular noncompaction 7	2016-11-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000033170	SCV004041497	likely pathogenic	Left ventricular noncompaction 7	2023-03-08	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000033170	SCV005061574	likely pathogenic	Left ventricular noncompaction 7	2024-05-20	criteria provided, single submitter	clinical testing	We observed a heterozygous NM_020774.4:c.1588C>T (p.Arg530*) genetic variant in the MIB1 gene on WES data in a sporadic case of Sudden Unexplained Nocturnal Death Syndrome (SUNDS) in 15 y.o. male adolescent. The c.1588C>T (p.Arg530*) genetic variant is in The Genome Aggregation Database (gnomAD) v2.1.1 and v4.1.0 with total MAF 0.00004598 and 0.00003965 respectively (Date of access 18-06-2023). ClinVar contains an entry for this variant (Variation ID: 40092). This variant leads to NMD of the mutant transcript according to in silico predictors and Luxán et al. (2013) experimental data (PMID: 23314057). Based on these evidences, we consider it to classify this variant as Likely Pathogenic.
OMIM	RCV000033170	SCV000056952	pathogenic	Left ventricular noncompaction 7	2013-02-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000485600	SCV001742100	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000485600	SCV001920358	likely pathogenic	not provided		no assertion criteria provided	clinical testing