Submissions for variant NM_001368067.1(LDB3):c.439G>A (p.Ala147Thr)

dbSNP: rs121908333

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255980	SCV000322056	pathogenic	not provided	2020-11-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate disruption of the actin cytoskeleton in mouse muscle cells (Lin et. al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16427346, 32721234, 23263837, 15668942, 24668811, 18765652, no PMID, 19377068, 27546599, 28349680, 21676617)
Invitae	RCV000004992	SCV000545674	pathogenic	Myofibrillar myopathy 4	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 147 of the LDB3 protein (p.Ala147Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant myofibrillar myopathy (PMID: 15668942, 23263837). ClinVar contains an entry for this variant (Variation ID: 4727). 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. Experimental studies have shown that this missense change affects LDB3 function (PMID: 24668811). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770149	SCV000901575	uncertain significance	Cardiomyopathy	2020-04-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255980	SCV001247302	pathogenic	not provided	2022-05-01	criteria provided, single submitter	clinical testing	LDB3: PP1:Strong, PM2, PS4:Moderate, PP3, PS3:Supporting
Athena Diagnostics	RCV000255980	SCV001476528	pathogenic	not provided	2022-04-21	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with myofibrillar myopathy and appears to segregate with disease in at least one family.
Revvity Omics, Revvity	RCV000255980	SCV002017102	likely pathogenic	not provided	2023-03-31	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000004992	SCV002498642	likely pathogenic	Myofibrillar myopathy 4	2021-08-10	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace alanine with threonine at codon 147 of the LDB3 protein (p.(Ala147Thr), also known as NM_007078.2:c.690-4733G>A). The alanine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the striated muscle ZASP-like motif in exon 6 of the skeletal muscle isoform (PMID: 28349680). There is a small physicochemical difference between alanine and threonine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). It has been identified in multiple individuals with myofibrillar myopathy, including variable cardiac and neuropathic involvement, and segregates with disease in at least one large family (PMID: 15668942, 18765652, 21676617, 23263837, 32721234). The variant demonstrates isoform-specific disruption of skeletal muscle actin filaments in functional assays (PMID: 24668811). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/4 algorithms predict benign). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4_Moderate, PP1_Moderate, PS3_Supporting, PM2_Supporting.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000004992	SCV002768075	pathogenic	Myofibrillar myopathy 4	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is the proposed mechanism of disease in this gene and is associated with myofibrillar myopathy 4 (MIM#609452). (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 threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (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) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with myofibrillar myopathy (ClinVar, PMID: 18055494). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000004992	SCV000025168	pathogenic	Myofibrillar myopathy 4	2005-02-01	no assertion criteria provided	literature only
GenomeConnect - Invitae Patient Insights Network	RCV003483424	SCV004228663	not provided	Dilated cardiomyopathy 1C; Myofibrillar myopathy 4		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-08-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.