Submissions for variant NM_001368067.1(LDB3):c.370C>A (p.Pro124Thr)

gnomAD frequency: 0.00005  dbSNP: rs755513516

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183549	SCV000236018	uncertain significance	not provided	2020-05-20	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 201860; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Invitae	RCV000536810	SCV000638674	uncertain significance	Myofibrillar myopathy 4	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 124 of the LDB3 protein (p.Pro124Thr). This variant is present in population databases (rs755513516, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of LDB3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 201860). 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 tolerated. 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623559	SCV000740596	uncertain significance	Primary familial dilated cardiomyopathy	2017-03-30	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470803	SCV002768111	uncertain significance	Dilated cardiomyopathy 1C	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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 proline to threonine. (I) 0219 - This variant is non-coding in alternative transcripts, including the predominantly reported in ClinVar, NM_007078.3, which has higher expression in heart tissues (GTEx). However, it is coding in other transcripts expressed in cardiac tissue (GTEx). (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (7 heterozygotes, 0 homozygotes). (SP) 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) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS 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
Revvity Omics, Revvity	RCV000183549	SCV003816497	uncertain significance	not provided	2020-05-05	criteria provided, single submitter	clinical testing