Submissions for variant NM_024334.3(TMEM43):c.679C>G (p.His227Asp)

gnomAD frequency: 0.00005  dbSNP: rs201460674

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000998000	SCV001153805	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170682	SCV001333276	uncertain significance	Cardiomyopathy	2018-02-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170682	SCV001357901	uncertain significance	Cardiomyopathy	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with aspartic acid at codon 227 of the TMEM43 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/282672 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.
Invitae	RCV001210003	SCV001381466	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 227 of the TMEM43 protein (p.His227Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TMEM43-related conditions. ClinVar contains an entry for this variant (Variation ID: 809431). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM43 protein function. 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.
GeneDx	RCV000998000	SCV001826127	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Fulgent Genetics, Fulgent Genetics	RCV002479182	SCV002794058	uncertain significance	Arrhythmogenic right ventricular dysplasia 5; Emery-Dreifuss muscular dystrophy 7, autosomal dominant; Auditory neuropathy, autosomal dominant 3	2021-07-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003160147	SCV003860926	likely benign	Cardiovascular phenotype	2022-12-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.