Submissions for variant NM_007078.3(LDB3):c.1051A>G (p.Thr351Ala)

gnomAD frequency: 0.00026  dbSNP: rs138251566

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038717	SCV000062395	likely benign	not specified	2017-06-28	criteria provided, single submitter	clinical testing	p.Thr351Ala in exon 10 of LDB3: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including multiple mamm als. In addition, this variant has been identified in 0.08% (27/34356) of Latino and 0.06% (78/124442) of European chromosomes Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org/; dbSNP rs138251566), and in individuals wi th different, non-overlapping cardiomyopathies, including two individuals with a disease-causing variant sufficient to cause their disease (LMM data).
GeneDx	RCV000656853	SCV000235985	uncertain significance	not provided	2021-03-04	criteria provided, single submitter	clinical testing	Reported in association with non-compaction dilated cardiomyopathy (Arbustini et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 36942; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31078652, 17438604, 33633783, 23299917, 27896284, 20474083, 25616123, 25041374, 29517769)
Invitae	RCV001081104	SCV000638663	likely benign	Myofibrillar myopathy 4	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618275	SCV000737378	likely benign	Cardiovascular phenotype	2020-03-23	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769285	SCV000900663	likely benign	Cardiomyopathy	2021-08-11	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000853422	SCV000996333	likely benign	Hypertrophic cardiomyopathy	2017-03-16	criteria provided, single submitter	research	The LDB3 Thr351Ala has been reported before in an an ARVD/C proband, and was found to cosegregate to two siblings diagnosed with ARVD/C (Lopez JM, et al., 2014). This variant has also been found in a 62yo male patient with severe dilated cardiomyopathy with non-compaction (Arbustini E, et al., 2007) and a HCM patient with another likely causal variant (LMM ClinVar; SCV000062395.4). It is present in the 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), at an allele frequency >0.0004, which is higher then expected for an inherited heart disease. We identified this variant in a HCM proband with no family history of HCM or SCD. Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be non-deleterious. In summary, based on a high allele frequency in the general population and in silico tools predicting no functional affect on the protein, we classify LDB3 Thr351Ala as "likely benign".
CeGaT Center for Human Genetics Tuebingen	RCV000656853	SCV001150621	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	LDB3: BP4
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256803	SCV001433256	uncertain significance	Dilated cardiomyopathy 1A	2020-02-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003934861	SCV004750977	likely benign	LDB3-related disorder	2023-05-24	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000038717	SCV000280175	uncertain significance	not specified	2013-07-05	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LDB3 p.Thr351Ala Arbustini et al (2007) submitted a brief report to Human Genetics on this variant as a novel variant seen in a 62-year-old male with “noncompaction dilated cardiomyopathy.” I also found a conference abstract in Italian that appears to report the variant in a patient with LVNC (Tripodi et al 2010 71st Congresso Nazionale della Societa Italiana di Cardiologia). A translation via Google translate indicates the authors report the p.Thr351Ala variant in a 41-year old male with LVNC. No segregation or function data was provided in either report. Vatta et al (2003) reported a variant (p.Ile352Met) at the neighboring codon that was present in all five family members with DCM and absent in 200 controls. They predicted that this variant would “abolish an alpha-helix a short beta-sheet.” Another nearby variant (p.Thr350Ile) has been reported in a case of a child with Barth Syndrome (Marziliano et al 2007). That patient also had a nonsense variant in TAZ. Interestingly, the patient’s brother and father both carried the p.Thr350Ile LDB3 variant and had non-compaction on echo, though not severe enough to make diagnostic criteria for LVNC. Arbustini et al (2007) also reported that another patient with “noncompaction dilated cardiomyopathy” had a variant in another nearby codon (p.Thr358Ala). The p.Thr351Ala variant in LDB3 is a non conservative amino acid change with a polar, neutral Threonine replaced with a non polar neutral Alanine. In silico analysis (PolyPhen and SIFT) predicts the variant to be benign and tolerated respectively. While the cases reviewed above do not include HCM, variants in LDB3 have been implicated in HCM. Tripodi et al (2010) did not observe the variant in either 150 or 300 control individuals (difficult to tell in the translated text). No other control data is available, however the variant is not reported in dbSNP (checked March 2nd, 2011) Based on these data, this variant may cause cardiomyopathy, though there is insufficient data available to support predictive genetic testing in at-risk family members.