Submissions for variant NM_017636.4(TRPM4):c.2665del (p.His889fs)

dbSNP: rs777047595

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486592	SCV000572365	uncertain significance	not provided	2020-02-25	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 422801; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30847666)
Invitae	RCV000645471	SCV000767216	uncertain significance	Progressive familial heart block type IB	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His889Thrfs*35) in the TRPM4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TRPM4 cause disease. This variant is present in population databases (rs777047595, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 422801). 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.
Illumina Laboratory Services, Illumina	RCV000645471	SCV000915841	uncertain significance	Progressive familial heart block type IB	2017-09-01	criteria provided, single submitter	clinical testing	The TRPM4 c.2665delC (p.His889ThrfsTer35) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for progressive familial heart block. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Ambry Genetics	RCV002455933	SCV002739498	uncertain significance	Cardiovascular phenotype	2023-06-13	criteria provided, single submitter	clinical testing	The c.2665delC variant, located in coding exon 18 of the TRPM4 gene, results from a deletion of one nucleotide at nucleotide position 2665, causing a translational frameshift with a predicted alternate stop codon (p.H889Tfs*35). This variant was detected in an arrhythmia genetic testing cohort; however, clinical details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309).This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TRPM4 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002489168	SCV002781024	uncertain significance	Progressive familial heart block type IB; Erythrokeratodermia variabilis et progressiva 6	2021-10-20	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318377	SCV004021982	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PVS1_Moderate
Breakthrough Genomics, Breakthrough Genomics	RCV000486592	SCV005194740	uncertain significance	not provided		criteria provided, single submitter	not provided