Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000156502 | SCV000206221 | uncertain significance | not specified | 2014-05-01 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The 93+1G>T var iant in LDB3 has not been previously reported in any other families with cardiom yopathy or myopathy. It was also absent from large population studies. This vari ant occurs in the invariant region (+/- 1, 2) of the splice consensus sequence a nd is predicted to cause altered splicing leading to an abnormal or absent prote in. Mouse studies indicate that the spectrum of phenotypes resulting from homozy gous loss-of-function (LOF) of LDB3 include DCM and congenital myopathy (Zhou 20 01, Zheng 2009), however heterozygous LOF has not been well studied. Our laborat ory has previously identified 5 predicted LOF variants that are also expected to lead to an abnormal or absent protein; 1 was identified in a heterozygous adult with VT and SCA, 1 was identified in a heterozygous infant with DCM, 3 were ide ntified in compound heterozygous or homozygous infant with DCM +/- noncompaction . In summary, the predicted impact to the protein increases the likelihood that this variant is pathogenic, but additional studies are required to fully establi sh its clinical significance. |
| Invitae | RCV003611498 | SCV004409678 | uncertain significance | Myofibrillar myopathy 4 | 2022-11-16 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 179706). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the LDB3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in LDB3 cause disease. |