Submissions for variant NM_007078.3(LDB3):c.826C>T (p.Arg276Cys)

gnomAD frequency: 0.00015  dbSNP: rs397517226

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000639877	SCV000761460	uncertain significance	Myofibrillar myopathy 4	2023-08-23	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 45556). This variant is also known as Arg276Cys. This variant is present in population databases (rs397517226, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 229 of the LDB3 protein (p.Arg229Cys).
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000991353	SCV001142722	uncertain significance	Hypertrophic cardiomyopathy	2020-01-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496619	SCV002775867	uncertain significance	Dilated cardiomyopathy 1C; Myofibrillar myopathy 4	2021-07-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003380404	SCV004096674	uncertain significance	Cardiovascular phenotype	2023-06-21	criteria provided, single submitter	clinical testing	The p.R276C variant (also known as c.826C>T), located in coding exon 5 of the LDB3 gene, results from a C to T substitution at nucleotide position 826. The arginine at codon 276 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with dilated cardiomyopathy; however, details were limited (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV004719677	SCV005325976	uncertain significance	not provided	2023-07-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27532257)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038770	SCV000062448	uncertain significance	not specified	2009-04-20	no assertion criteria provided	clinical testing
Cytogenetics- Mohapatra Lab, Banaras Hindu University	RCV001293339	SCV001481927	pathogenic	Dilated cardiomyopathy 1C	2014-08-20	no assertion criteria provided	case-control