Submissions for variant NM_007078.3(LDB3):c.1594G>C (p.Ala532Pro)

gnomAD frequency: 0.00036  dbSNP: rs143764931

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767126	SCV000236007	likely benign	not provided	2020-09-18	criteria provided, single submitter	clinical testing	Reported in association with HCM (Lopes et al., 2015); however, no specific clinical details were provided; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 201852; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25351510)
Invitae	RCV001079637	SCV000261974	likely benign	Myofibrillar myopathy 4	2024-01-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000183539	SCV000271909	likely benign	not specified	2020-01-08	criteria provided, single submitter	clinical testing	The p.Ala532Pro variant in LDB3 is classified as likely benign because it has been identified in 0.07% (85/128298) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org; dbSNP rs143764931). In addition, alanine (Ala) at position 532 is not conserved in evolution and proline (Pro) is present at this position in >10 bird and reptile species. ACMG/AMP Criteria applied: BS1.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769289	SCV000900667	likely benign	Cardiomyopathy	2021-03-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000767126	SCV002049643	uncertain significance	not provided	2021-04-14	criteria provided, single submitter	clinical testing	The LDB3 c.1594G>C; p.Ala532Pro variant (rs143764931) is reported in the literature in a cohort of individuals affected with hypertrophic cardiomyopathy, though it was not demonstrated to cause disease (Lopes 2015). This variant is found in the non-Finnish European population with an overall allele frequency of 0.07% (85/128298 alleles) in the Genome Aggregation Database. The alanine at codon 532 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.244). Given the lack of clinical and functional data, the significance of the p.Ala532Pro variant is uncertain at this time. References: Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. PMID: 25351510.
Ambry Genetics	RCV002399674	SCV002709730	likely benign	Cardiovascular phenotype	2022-05-16	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470802	SCV002769435	likely benign	Familial isolated dilated cardiomyopathy	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (92 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported once in a hypertropic cardiomyopathy cohort study (PMID: 23396983), and has also been previously observed twice in our HCM patient cohort and once in our ARVC patient cohort in patients harbouring pathogenic variants. Additionally, it has been reported as VUS and likely benign in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000767126	SCV003916617	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	LDB3: BS1