ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.896G>C (p.Arg299Thr) (rs139590716)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619604 SCV000734937 likely benign Cardiovascular phenotype 2017-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
Color RCV000771951 SCV000904904 benign Cardiomyopathy 2018-06-11 criteria provided, single submitter clinical testing
GeneDx RCV000183927 SCV000236415 likely benign not specified 2017-07-04 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000183927 SCV000918312 benign not specified 2018-06-18 criteria provided, single submitter clinical testing Variant summary: TMEM43 c.896G>C (p.Arg299Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function (MutationTaster not captured due to low p-value). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 520-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in TMEM43 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.896G>C, has been reported in the literature in individuals affected with Arrhythmia (Honda_2016, Liang_2011), predominantly observed with another TMEM43 variant, p.V89M (reported by ClinVar as likely benign). In addition, an unaffected mother was found to carry the variant and the V89M variant, showing a lack of cosegregation with disease (Liang_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000642434 SCV000764112 benign Arrhythmogenic right ventricular cardiomyopathy, type 5 2017-12-24 criteria provided, single submitter clinical testing

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