Submissions for variant NM_007078.3(LDB3):c.1978+2_1978+5del

dbSNP: rs1554864768

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599045	SCV000710208	uncertain significance	not provided	2018-09-19	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the LDB3 gene. The c.1978+2_1978+5delTAGG variant has not been reported as a pathogenic or benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). This 4 nucleotide deletion destroys the intron 11 splice donor site and is predicted to result in aberrant splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. In addition, the majority of reported pathogenic variants in the LDB3 gene are missense changes (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV001312897	SCV001503370	uncertain significance	Myofibrillar myopathy 4	2022-06-20	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 12 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. The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.2, and corresponds to NM_001080116.1:c.*19475_*19478del in the primary transcript.