Submissions for variant NM_024334.3(TMEM43):c.859C>T (p.His287Tyr)

gnomAD frequency: 0.00001  dbSNP: rs780299346

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183941	SCV000236433	uncertain significance	not provided	2019-12-23	criteria provided, single submitter	clinical testing	Reported in a patient with sudden unexplained death; however, no additional clinical information was provided (Lin et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 202121; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29247119)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697685	SCV000826310	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 287 of the TMEM43 protein (p.His287Tyr). This variant is present in population databases (rs780299346, gnomAD 0.0009%). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29247119). ClinVar contains an entry for this variant (Variation ID: 202121). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Color Diagnostics, LLC DBA Color Health	RCV001184035	SCV001349907	uncertain significance	Cardiomyopathy	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 287 of the TMEM43 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TMEM43-related disorders in the literature. This variant has been identified in 1/250388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001184035	SCV002043565	uncertain significance	Cardiomyopathy	2019-07-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000697685	SCV004841572	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 287 of the TMEM43 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden unexplained death (PMID: 29247119), as well as in an individual who did not have cardiovascular symptoms (PMID: 31604776). This variant has been identified in 1/250388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000183941	SCV005879897	uncertain significance	not provided	2024-11-14	criteria provided, single submitter	clinical testing	The TMEM43 c.859C>T; p.His287Tyr variant (rs780299346, ClinVar Variation ID: 202121) is reported in the literature in one case of sudden unexplained death and in one individual with mitochondrial myopathy that lacked cardiovascular symptoms (Lin 2017, Schultz-Rogers 2019). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is neutral (REVEL: 0.057). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Lin Y et al. Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. Circ Cardiovasc Genet. 2017 Dec;10(6):e001839. PMID: 29247119. Schultz-Rogers L et al. Novel biallelic variants in MSTO1 associated with mitochondrial myopathy. Cold Spring Harb Mol Case Stud. 2019 Dec 13;5(6):a004309. PMID: 31604776.
Ambry Genetics	RCV005286038	SCV005949563	likely benign	Cardiovascular phenotype	2025-02-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.