Submissions for variant NM_001368067.1(LDB3):c.494C>T (p.Ala165Val)

dbSNP: rs121908334

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036847	SCV000060502	pathogenic	Neuromuscular disease	2018-11-21	criteria provided, single submitter	clinical testing	The p.Ala165Val variant in LDB3 has been reported in at least 6 individuals with myofibrillar myopathy and segregated with disease in 9 affected individuals fro m 1 family (Selcen 2005, Griggs 2007, Fischer 2008, Vincent 2016, LMM data). It has also been identified in 1/113280 of European chromosomes by gnomAD (http://g nomad.broadinstitute.org) and reported in ClinVar (Variant ID #4728). An in vitr o function study showed that this variant disrupted Ankrd2 binding (Martinelli 2 014) and a study of mouse myoblasts transfected with the p.Ala165Val mutation sh owed a disrution of Z-disc structure and an accumulation of F-actin (Lin 2014). In summary, this variant meets criteria to be classified as pathogenic for autos omal dominant myofibrillar myopathy. ACMG/AMP criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate.
GeneDx	RCV000493600	SCV000582060	pathogenic	not provided	2022-06-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: Z-disc disruption and F-actin accumulation in mouse skeletal muscle, and disruption in the actin cytoskeleton in muscle cells (Lin et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28269794, 19377068, 27546599, 27618136, 25208129, 27638134, 18765652, 15668942, 33742095, 31791368, 21676617, 32419263, 31589614, 17337483, 24668811)
Athena Diagnostics	RCV000493600	SCV000613999	pathogenic	not provided	2014-12-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769278	SCV000900654	uncertain significance	Cardiomyopathy	2020-04-23	criteria provided, single submitter	clinical testing
Invitae	RCV000004993	SCV000965091	pathogenic	Myofibrillar myopathy 4	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 165 of the LDB3 protein (p.Ala165Val). This variant is present in population databases (rs121908334, gnomAD 0.0009%). This missense change has been observed in individuals with myofibrillar myopathy (PMID: 15668942, 25208129). ClinVar contains an entry for this variant (Variation ID: 4728). 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: 24647531, 24668811). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000493600	SCV001247303	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	LDB3: PM2, PP1:Moderate, PS3:Moderate, PS4:Moderate, PP3, PP4
Revvity Omics, Revvity	RCV000493600	SCV002017104	pathogenic	not provided	2022-07-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000004993	SCV002038571	pathogenic	Myofibrillar myopathy 4	2021-04-07	criteria provided, single submitter	clinical testing	The LDB3 c.494C>T (p.Ala165Val) variant, also referred to as c.690-4678C>T, is a missense variant that has been reported in at least seven unrelated individuals with myofibrillar myopathy presenting with progressive muscle weakness, mainly distally, and myopathic motor unit potentials noted through electromyography. Muscle atrophy, tripping episodes, walking difficulty, peripheral neuropathy, decreased reflexes in the legs, tingling and numbness in the feet, and ankle movement problems were also noted in some individuals (Selcen and Engler 2005; Griggs et al. 2007; Fischer et al. 2008; Semmler et al. 2014). Only one individual had cardiac problems presenting as prolonged QT (Selec and Engler 2005). The p.Ala165Val variant segregated with disease in a large pedigree where six affected individuals carried the variant. Three additional family members who carried the variant were asymptomatic at the time of the study, but they ranged in age from 39-49 years (Griggs et al. 2007). In functional studies using a mouse model or cells derived from mice, the phenotype observed in humans was recapitulated when the p.Ala165Val variant was present in a heterozygous state. This included presence of muscle weakness, characteristic muscle fiber structural abnormalities, protein aggregation patterns, and Z-disc disruption generally observed in myofibrillar myopathy (Lin et al. 2014; Pathak et al. 2014). The p.Ala165Val variant is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database, but this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence, the p.Ala165Val variant is classified as pathogenic for myofibrillar myopathy.
Mendelics	RCV002247249	SCV002516647	pathogenic	Dilated cardiomyopathy 1C	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162208	SCV003861769	pathogenic	Cardiovascular phenotype	2022-11-07	criteria provided, single submitter	clinical testing	The c.690-4678C>T intronic pathogenic mutation results from a C to T substitution 4678 nucleotides upstream from coding exon 5 in the LDB3 gene. This alteration, also known as c.494C>T p.A165V in isoform NM_001080116, has been detected in multiple individuals with myofibrillar myopathy and has been reported to segregate with disease (Selcen D et al. Ann. Neurol., 2005 Feb;57:269-76; Griggs R et al. Brain, 2007 Jun;130:1477-84; Olivé M et al. Neuromuscul. Disord., 2011 Aug;21:533-42; Semmler AL et al. Orphanet J Rare Dis, 2014 Aug;9:121; Vincent AE et al. Neuromuscul. Disord., 2016 10;26:691-701). Haplotype analysis has demonstrated that this variant is a European founder mutation (Griggs R et al. Brain, 2007 Jun;130:1477-84). Functional analyses indicate that this alteration may impact protein function, but the physiological relevance of the observed impacts is unclear (Lin X et al. J. Biol. Chem., 2014 May;289:13615-26). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003934799	SCV004747584	pathogenic	LDB3-related disorder	2023-12-21	criteria provided, single submitter	clinical testing	The LDB3 c.494C>T variant is predicted to result in the amino acid substitution p.Ala165Val. This variant has been reported in individuals with myofibrillar myopathy and shown to segregate with disease in families (see, for example, Selcen and Engel. 2005. PubMed ID: 15668942; Griggs et al. 2007. PubMed ID: 17337483; Semmler et al. 2014. PubMed ID: 25208129). In vitro and in vivo experimental studies suggest this variant impacts protein function (Lin et al. 2014. PubMed ID: 24668811; Martinelli et al. 2014. PubMed ID: 24647531; Pathak et al. 2021. PubMed ID: 33742095). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in a large population database. This variant is interpreted as pathogenic.
OMIM	RCV000004993	SCV000025169	pathogenic	Myofibrillar myopathy 4	2007-06-01	no assertion criteria provided	literature only
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000239669	SCV000298022	pathogenic	Myofibrillar myopathy	2016-08-16	no assertion criteria provided	clinical testing