ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.1051A>G (p.Thr351Ala) (rs138251566)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2018-11-16 criteria provided, single submitter clinical testing The T351A variant of uncertain significance in the LDB3 gene has been previously reported in a 62 year-old Italian male diagnosed with non-compaction DCM (Arbustini et al., 2007). It has also been reported in seven members of one Spanish family in association with ARVC; four individuals with definite ARVC (including one obligate carrier), one individual with borderline ARVC, and two individuals with possible ARVC, per Task Force Criteria (Lopez-Ayala et al., 2014; Lopez-Ayala et al., 2015). This variant has also been observed in other individuals referred for cardiomyopathy genetic testing at GeneDx, although no segregation data are available. The T351A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, this variant is also observed in 27/34,356 (0.08%) alleles from individuals of Latino ancestry and in 78/124442 (0.06%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016).
Invitae RCV001081104 SCV000638663 likely benign Myofibrillar myopathy, ZASP-related 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618275 SCV000737378 uncertain significance Cardiovascular phenotype 2018-02-14 criteria provided, single submitter clinical testing Insufficient evidence;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769285 SCV000900663 uncertain significance Cardiomyopathy 2017-09-11 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 Praxis fuer Humangenetik Tuebingen RCV000656853 SCV001150621 uncertain significance not provided 2016-10-01 criteria provided, single submitter clinical testing
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
Integrated Genetics/Laboratory Corporation of America RCV000030617 SCV000053295 likely benign Primary dilated cardiomyopathy 2015-10-02 no assertion criteria provided clinical testing
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.

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