ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.664G>A (p.Ala222Thr) (rs139922045)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038764 SCV000062442 uncertain significance not specified 2014-04-22 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ala222Thr varia nt in LDB3 has been identified by our laboratory in 1 Caucasian infant with HCM, 1 Caucasian young adult with unspecified cardiomyopathy, and 1 Caucasian adult with HCM. This variant has also been identified in 4/8600 of European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs139922045). Computational prediction tools do not provide strong su pport for or against an impact to the protein. However, alanine (Ala) at positio n 222 is not conserved in evolution and the change to threonine (Thr) is present in several species (black flying fox, megabat, and lizard), suggesting that a c hange at this position may be tolerated. In summary, while the clinical signific ance of the Ala222Thr variant is uncertain, these data suggest that it is more l ikely to be benign.
GeneDx RCV000767125 SCV000235992 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing The A222T variant was reported in association with myofibrillar myopathy, sporadic inclusion body myositis and HCM (Semmler et al., 2014; Weihl et al., 2015; Lopes et al., 2015); however, no additional clinical details were provided. Additionally, this variant has been reported in a patient with LVNC who also harbored a nonsense variant in the TTN gene (Miszalski-Jamka et al., 2017). The A222T variant has been identified independently and/or in conjunction with additional cardiogenetic variants in other individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data are limited or absent for these individuals. The A222T 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. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Lastly, A222T was observed in 91/122,516 (0.07%) alleles from individuals of European (Non-Finnish) background from large population cohorts (Lek et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000767125 SCV000638671 likely benign not provided 2019-02-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617985 SCV000736714 uncertain significance Cardiovascular phenotype 2018-01-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000763673 SCV000894553 uncertain significance Dilated cardiomyopathy 1C; Myofibrillar myopathy, ZASP-related 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000767125 SCV001150613 uncertain significance not provided 2017-09-01 criteria provided, single submitter clinical testing

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