Submissions for variant NM_024334.3(TMEM43):c.748G>A (p.Gly250Ser)

gnomAD frequency: 0.00003  dbSNP: rs371797765

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558508	SCV000642106	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 250 of the TMEM43 protein (p.Gly250Ser). This variant is present in population databases (rs371797765, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. 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: 466423). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170684	SCV001333278	likely benign	Cardiomyopathy	2018-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170684	SCV001343055	likely benign	Cardiomyopathy	2018-11-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002395393	SCV002672699	likely benign	Cardiovascular phenotype	2023-11-01	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.
CeGaT Center for Human Genetics Tuebingen	RCV003311839	SCV004011446	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	TMEM43: BP4
All of Us Research Program, National Institutes of Health	RCV000558508	SCV004841556	likely benign	Arrhythmogenic right ventricular dysplasia 5	2023-12-01	criteria provided, single submitter	clinical testing