Submissions for variant NM_024334.3(TMEM43):c.564C>T (p.Gly188=)

gnomAD frequency: 0.00024  dbSNP: rs143124744

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000251873	SCV000319704	likely benign	Cardiovascular phenotype	2015-05-27	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464528	SCV000545861	likely benign	Arrhythmogenic right ventricular dysplasia 5	2024-12-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825843	SCV000967322	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Gly188Gly in Exon 07 of TMEM43: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence. It has been identified in 0.1% (3/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs143124744).
Color Diagnostics, LLC DBA Color Health	RCV001178588	SCV001343065	likely benign	Cardiomyopathy	2018-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001556223	SCV001777760	uncertain significance	not provided	2021-09-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports a deleterious effect on splicing; Reported in ClinVar (ClinVar Variant ID# 264054; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825843	SCV003801186	likely benign	not specified	2023-01-16	criteria provided, single submitter	clinical testing	Variant summary: TMEM43 c.564C>T alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates/strengthens a cryptic 5' donor site and also predict the variant weakens/abolishes a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.2e-05 in 251472 control chromosomes, found exclusively within the African or African-American subpopulation at a frequency of 0.0008 in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 96 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM43 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (8.3e-06), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.564C>T in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely benign (n=3) or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign until further evidence is available to determine the variant effect on normal splicing and function.
PreventionGenetics, part of Exact Sciences	RCV004748679	SCV005345262	likely benign	TMEM43-related disorder	2023-03-14	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).