ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.83G>A (p.Arg28Gln) (rs757651177)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000550780 SCV000642108 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 5 2017-05-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 28 of the TMEM43 protein (p.Arg28Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs757651177, ExAC 0.001%) but has not been reported in the literature in individuals with a TMEM43-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786222 SCV000924960 uncertain significance not provided 2017-06-12 no assertion criteria provided provider interpretation Found at our center in an infant being evaluated for LQTS, which is not a condition associated with the TMEM43 gene. He had an Arrhythmia Comprehensive Panel with the Invitae laboratory. One variant was reported: TMEM43, Exon 2, c.83G>A (p.Arg28Gln; R28Q), heterozygous (NM_024334.2) Chromosome position: 3:14170982 G / A Based on the information reviewed below, we classify this as a VUS, probably benign, concluding that it should not be used for diagnosis or for predictive testing. This variant has not previously been reported in the literature in association with disease. Another variant at this same codon, p.Arg28Trp, however, is currently listed in ClinVar as Benign by LMM, Invitae, Ambry, and GeneDx laboratories, which suggests that this codon may be tolerant of change. This is a nonconservative sequence change that replaces a positively-charged arginine with a polar glutamine at codon 28. The arginine residue is highly conserved across vertebrates, although it is a Lysine in at least one species of fish. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant is present in 6 out of ~140,000 individuals in the gnomAD database. Specifically, it is present in 2 African, 1 South Asian, 1 Latino, and 2 non-Finnish European individuals in gnomAD. Overall MAF in the population is 0.002%. Highest ethnicity-specific MAF is 0.008% in individuals with African ancestry. Of note, another variant at this same codon, p.Arg28Trp, is considered benign by multiple clinical labs and has an overall MAF of 0.3%, with a MAF of over 1% in some ethnicities.

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