ClinVar Miner

Submissions for variant NM_024334.3(TMEM43):c.347G>A (p.Arg116Gln)

gnomAD frequency: 0.00021  dbSNP: rs143535006
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246391 SCV000320604 benign Cardiovascular phenotype 2022-04-08 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
Invitae RCV000530636 SCV000642095 uncertain significance Arrhythmogenic right ventricular dysplasia 5 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 116 of the TMEM43 protein (p.Arg116Gln). This variant is present in population databases (rs143535006, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TMEM43-related conditions. ClinVar contains an entry for this variant (Variation ID: 264584). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TMEM43 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV001711848 SCV000725107 likely benign not provided 2021-03-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000614606 SCV000918313 benign not specified 2018-07-09 criteria provided, single submitter clinical testing Variant summary: TMEM43 c.347G>A (p.Arg116Gln) results in a conservative amino acid change located outside of any known functional domain or repeat of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-05 in 277098 control chromosomes, predominantly at a frequency of 0.00058 within the African subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 23.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM43 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The c.347G>A has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been reported (TTR c.424G>A, p.Val142Ile), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health RCV001176073 SCV001339909 likely benign Cardiomyopathy 2019-12-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000614606 SCV001365472 benign not specified 2019-09-27 criteria provided, single submitter clinical testing The p.Arg116Gln variant in TMEM43 is classified as benign because it has been identified in 0.06% (17/24938) of African chromosomes and 1 homozygote by gnomAD (http://gnomad.broadinstitute.org). In addition, 3 mammals carry glutamine (Gln) at this position despite high nearby amino acid conservation. ACMG/AMP Criteria applied: BP4_Strong.ACMG/AMP Criteria applied: BS1, BP4_Strong.

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