ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.640-10A>G (rs80356807)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057437 SCV000234730 pathogenic not provided 2021-02-10 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Published functional studies using RT-PCR demonstrate a damaging effect as this variant alters the splice acceptor site of intron 3 in the LMNA, which leads to an abnormal message RNA (Otomo et al., 2005); This variant is associated with the following publications: (PMID: 16965317, 30597161, 24459210, 24846508, 20474083, 15720451, 22337857, 28044975, 28679633, 32408651)
Invitae RCV001221904 SCV001393973 pathogenic Charcot-Marie-Tooth disease, type 2 2019-10-09 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. This variant is present in population databases (rs80356807, ExAC 0.006%). This variant has been observed to segregate with cardiac conduction defects and dilated cardiomyopathy in a large family (PMID: 15720451). ClinVar contains an entry for this variant (Variation ID: 66921). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 15720451, 28679633). For these reasons, this variant has been classified as Pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057437 SCV000088551 not provided not provided no assertion provided not provided
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000057437 SCV000280183 likely pathogenic not provided 2013-01-27 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LMNA IVS3-10 A>G Based on the evidence reviewed below, we classify this variant as likely disease causing. This variant has previously been reported in just one family, with strong segregation data. Otomo et al. (2005) reported that this splice site variant segregated with disease in 7 members of a large Japanese family. The family phenotype included progressive AV block, atrial fibrillation, DCM, and heart failure. This is a change in the splice-acceptor site at intron 3 of the LMNA gene, which appears to result in abnormal splicing. Otomo et al. (2005) used RT-PCR to show that the IVS3-10 A>G variant alters the splice acceptor site at intron 3, leading to an abnormal mRNA. Other splice site mutations in the LMNA gene have also been reported in association with DCM or laminopathy . In total the variant has not been seen in >5350 published controls and publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals. c.640-10 A>G is not listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP); however, an A>C change at c.640-10 is listed in dbSNP as rs80356807 and appears to have been found clinically in a patient with Emery-Dreifuss Muscular Dystrophy (but clinical significance reads: “with non-pathogenic allele”). The variant is not listed in 1000 genomes (http://browser.1000genomes.org/index.htm) as of May 13, 2012. The variant was not observed in published controls: Otomo et al. (2005) did not observe the variant in 50 Japanese controls. GeneDx did not report controls.
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV001029824 SCV001192607 pathogenic Dilated cardiomyopathy 1A 2019-06-25 no assertion criteria provided clinical testing

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