ClinVar Miner

Submissions for variant NM_017636.4(TRPM4):c.2740A>T (p.Lys914Ter) (rs140799936)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227434 SCV000290322 likely benign Progressive familial heart block type 1B 2017-12-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000387261 SCV000414306 uncertain significance TRPM4-Related Disorders 2016-06-14 criteria provided, single submitter clinical testing The c.2740A>T (p.Lys914Ter) variant is a stop gained variant that has been reported in at least two studies in which it is found in a heterozygous state in a total of four patients with Brugada syndrome (Liu et al. 2012; Hertz et al. 2015). The p.Lys914Ter variant was reported in two of 1914 controls (Liu et al. 2012) and is reported at a frequency of 0.00221 in the European (Non-Finnish) population of the Exome Aggregation Consortium. There is limited evidence linking the TRPM4 gene to Brugada syndrome. Functional analysis of the p.Lys914Ter variant protein in HEK-293 cells demonstrated the variant resulted in decreased total expression, a truncated protein and a lack of current in a single channel conductance test (Liu et al. 2012). Due to the potential impact of stop-gained variants and the evidence from the literature, the p.Lys914Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for TRPM4-related disorders.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000419640 SCV000510701 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
GeneDx RCV000419640 SCV000514972 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing The K914X variant in the TRPM4 gene has been reported in both Brugada syndrome patients and control subjects (Liu et al., 2013; Hertz et al., 2013; Ghouse et al., 2017). Lui et al. (2013) initially reported this variant in three Brugada syndrome patients and demonstrated K914X resulted in decreased expression of the TRPM4 channel. However, a dominant effect was not established because the combined expression of wild-type and mutant TRPM4 channels was not studied (Lui et al., 2013). Subsequently, Hertz et al. (2015) described K914X as a likely pathogenic variant in a 37 year old male with palpitations, ventricular extrasystoles, and sudden unexplained death. Nevertheless, Ghouse et al. (2017) reported that K914X was present in 51/6,135 individuals in a Danish study cohort, higher than the phenotype frequency in the general population. This variant is also observed in 336/277,038 (0.01%) global alleles, including 247/126,580 (0.2%) European (non-Finnish) alleles, in large population cohorts (Lek et al., 2016). K914X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. However, only one other nonsense variant (W525X) has been reported in the Human Gene Mutation Database in association with disease (Stenson et al., 2014); the majority of pathogenic variants are missense substitutions, indicating haploinsufficiency is not a well established disease mechanism for the TRPM4 gene.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000419640 SCV000884740 likely benign not provided 2018-01-12 criteria provided, single submitter clinical testing The TRPM4 c.2740A>T; p.Lys914Ter was reported in three individuals as part of a cohort of 248 Brugada syndrome patients; however, the same study also detected the variant in two out of 1,914 healthy controls (Liu 2013). A review of electrocardiogram data of 51 Danish carriers of the p.Lys914Ter variant did not detect a significant J point elevation compared to noncarriers (Ghouse 2017). This variant introduces a premature termination codon in exon 18 and has been shown to result in a nonfunctional calcium channel in the absence of a wild-type allele (Liu 2013). It is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.2% (identified on 247 out of 126,580 chromosomes), and is classified as likely benign/unknown significance in ClinVar (ID 241177). Based on the available information, the p.Lys914Ter variant is likely to be benign.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852765 SCV000995483 likely benign Cardiomyopathy 2019-01-10 criteria provided, single submitter clinical testing

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