Submissions for variant NM_007078.3(LDB3):c.992C>T (p.Ala331Val)

gnomAD frequency: 0.00005  dbSNP: rs368053281

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001348153	SCV001542442	uncertain significance	Myofibrillar myopathy 4	2023-12-11	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.*7252C>T in the primary transcript. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 331 of the LDB3 protein (p.Ala331Val). This variant is present in population databases (rs368053281, gnomAD 0.04%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 1043971). 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.
GeneDx	RCV001528696	SCV001874047	likely benign	not provided	2021-01-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31983221)
Ambry Genetics	RCV002384485	SCV002691034	likely benign	Cardiovascular phenotype	2019-03-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003405580	SCV004114987	uncertain significance	LDB3-related disorder	2022-12-05	criteria provided, single submitter	clinical testing	The LDB3 c.992C>T variant is predicted to result in the amino acid substitution p.Ala331Val. This variant was reported in an individual with dilated cardiomyopathy (Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221). This variant is reported in 0.040% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-88466383-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001528696	SCV004563810	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	The LDB3 c.992C>T; p.Ala331Val variant (rs368053281) is reported in the literature in an individual affected with dilated cardiomyopathy, although it was not demonstrated to be disease causing (Mazzarotto 2020). This variant is found in the general population with an overall allele frequency of 0.006% (16/281,292 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.119). Due to limited information, the clinical significance of the p.Ala331Val variant is uncertain at this time. References: Mazzarotto F et al. Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. Circulation. 2020 Feb 4;141(5):387-398. PMID: 31983221.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528696	SCV001740874	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001528696	SCV001923910	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528696	SCV001932578	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528696	SCV001954686	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528696	SCV001966828	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001528696	SCV002036850	likely benign	not provided		no assertion criteria provided	clinical testing