ClinVar Miner

Submissions for variant NM_017636.4(TRPM4):c.2531G>A (p.Gly844Asp) (rs200038418)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000249699 SCV000320605 uncertain significance Cardiovascular phenotype 2017-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000434894 SCV000511321 uncertain significance not provided 2017-02-14 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
Invitae RCV000434894 SCV000560581 likely benign not provided 2018-12-26 criteria provided, single submitter clinical testing
GeneDx RCV000434894 SCV000566303 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing The G844D variant of uncertain significance in the TRPM4 gene has been reported in multiple individuals in association with cardiac conduction disorders (Liu et al., 2010; Stallmeyer et al., 2012; Liu, et al., 2013; Celestino-Soper et al., 2015; Daumy et al., 2016; Syam et al., 2016; Hof et al., 2017). However, several of these probands harbored additional cardiogenetic variants, and some of the relatives who were heterozygous for G844D were unaffected (Liu et al., 2010; Stallmeyer et al., 2012; Celestino-Soper et al., 2015). In addition, one of the probands was reported to be homozygous for G844D (Daumy et al., 2016). This variant is observed in 179/183122 (0.1%) alleles from individuals of multiple ethnic backgrounds in large population cohorts, indicating this may be a rare benign variant (Lek et al., 2016). Furthermore, in silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, G844D 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. Moreover, functional studies suggest that the G844D variant causes a gain-of-function effect due to an elevated TRPM4 channel density at the cell surface (Liu et al., 2010). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000434894 SCV000605446 uncertain significance not provided 2017-05-17 criteria provided, single submitter clinical testing The p.Gly844Asp variant (rs200038418) has been observed in several families with various cardiac conduction disturbances, including right bundle branch block (RBBB; Liu 2010 and Stallmeyer 2012), Brugada syndrome (BrS; Liu 2013) and atrioventricular block (AVB; Celestino-Soper 2015 and Syam 2016). However, multiple non-symptomatic carriers have been noted (Liu 2010 and Stallmeyer 2012) and this variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans of 0.155% (identified in 123 out of 79,180 chromosomes); a frequency used by the authors of Syam et al (2016) to conclude the p.Gly844Asp variant is a benign polymorphism. Functional studies of the p.Gly844Asp variant in HEK-293 cells indicate an increase in current density and channel surface expression (Liu 2010); however, whether these defects in vitro are relevant to disease manifestation in human patients is not completely understood. Accordingly, this variant is listed in the ClinVar database with multiple submitters classifying this variant as of uncertain clinical significance (Variation ID: 35489).Taken together, we conclude the clinical significance of the p.Gly844Asp variant cannot be determined with certainty. And at most, the genetic evidence is consistent with this variant being a low penetrance risk factor or genetic modifier of more penetrant alleles.
OMIM RCV000029161 SCV000051806 pathogenic Progressive familial heart block type 1B 2012-01-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.