Submissions for variant NM_007078.3(LDB3):c.1639C>T (p.Arg547Trp)

gnomAD frequency: 0.00002  dbSNP: rs374426474

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183540	SCV000236008	uncertain significance	not provided	2020-02-03	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in an alternate transcript of the the LDB3 gene. Although the R552W variant has not been published as pathogenic or been reported as benign to our knowledge, the R547W variant in the (NM_007078.2) transcript of the LDB3 gene has been identified in one individual referred for cardiomyopathy genetic testing at GeneDx and has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000736286.2; Landrum et al., 2016). The R552W variant is observed in 3/30,680 alleles (0.01%) from individuals of South Asian ancestry in large population cohorts (Lek et al., 2016). The R552W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Ambry Genetics	RCV000620630	SCV000736286	uncertain significance	Cardiovascular phenotype	2022-06-24	criteria provided, single submitter	clinical testing	The c.1639C>T (p.R547W) alteration is located in exon 9 (coding exon 9) of the LDB3 gene. This alteration results from a C to T substitution at nucleotide position 1639, causing the arginine (R) at amino acid position 547 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000183540	SCV001150627	uncertain significance	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Invitae	RCV001246465	SCV001419823	uncertain significance	Myofibrillar myopathy 4	2023-11-18	criteria provided, single submitter	clinical testing	The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*17360C>T in the primary transcript. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 547 of the LDB3 protein (p.Arg547Trp). This variant is present in population databases (rs374426474, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525887	SCV005039424	uncertain significance	not specified	2024-03-12	criteria provided, single submitter	clinical testing	Variant summary: LDB3 c.1639C>T (p.Arg547Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 248036 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1639C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 201853). Based on the evidence outlined above, the variant was classified as uncertain significance.