Submissions for variant NM_024334.3(TMEM43):c.323T>C (p.Val108Ala)

gnomAD frequency: 0.00002  dbSNP: rs182351748

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172119	SCV000051058	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152048	SCV000200641	uncertain significance	not specified	2015-03-12	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Val108Ala var iant in TMEM43 has been identified in 1 Asian individual with HCM, who carried a pathogenic variant in a different HCM gene (LMM unpublished data). It has also been identified in 0.2% (19/8584) of East Asian chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs182351748). Comp utational prediction tools and conservation analysis do not provide strong suppo rt for or against an impact to the protein. In summary, while the clinical signi ficance of the p.Val108Ala variant is uncertain, its frequency suggests that it is more likely to be benign.
GeneDx	RCV000172119	SCV000236444	uncertain significance	not provided	2019-08-14	criteria provided, single submitter	clinical testing	Reported in association with sudden arrhythmogenic death syndrome (SADS) and primary electric disease (PED) (Hata et al., 2016; Proost et al., 2017); Also reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23861362, 27005929, 28341588)
Color Diagnostics, LLC DBA Color Health	RCV001176806	SCV001340863	likely benign	Cardiomyopathy	2018-12-02	criteria provided, single submitter	clinical testing
Invitae	RCV001482753	SCV001687129	likely benign	Arrhythmogenic right ventricular dysplasia 5	2023-11-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444627	SCV002611782	benign	Cardiovascular phenotype	2021-07-13	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152048	SCV002766458	likely benign	not specified	2022-11-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895044	SCV004715813	likely benign	TMEM43-related condition	2022-05-04	criteria provided, single submitter	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).