ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.286C>G (p.Arg96Gly) (rs754797146)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621344 SCV000737039 uncertain significance Cardiovascular phenotype 2017-10-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000587222 SCV000236443 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing The R96G variant has not been published as a mutation or as a benign polymorphism to our knowledge. The R96G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the R96G 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. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions; however at least two models predict this variant likely does not alter the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2009), indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Integrated Genetics/Laboratory Corporation of America RCV000587222 SCV000699488 likely benign not provided 2017-01-30 criteria provided, single submitter clinical testing Variant summary: The TMEM43 c.286C>G (p.Arg96Gly) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 27/119640 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.002257 (26/11522). This frequency is about 226 times the estimated maximal expected allele frequency of a pathogenic TMEM43 variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance, without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.
Invitae RCV000541853 SCV000642093 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 5 2017-06-15 criteria provided, single submitter clinical testing

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