Incidentalome

Gene: TMEM43

reviewed by ClinGen Expert panel (published in 2021 PMID: 33831308) - DEFINITIVE
From PMID 33831308: The TMEM43 (transmembrane protein 43) gene encodes a nuclear membrane protein. One heterozygous pathogenic variant (NM_024334.3(TMEM43):c.1073C>T; p.Ser358Leu) was identified as a founder mutation in a large number of patients and families from Newfoundland, Denmark and Germany and has also been identified in other populations15,22. It is associated with a highly penetrant and arrhythmogenic subtype of ARVC in which biventricular involvement can often be appreciated. Evidence of pathogenicity of other TMEM43 variants remains limited.

Created: 27 May 2021, 5:25 a.m. | Last Modified: 27 May 2021, 5:25 a.m.

Panel Version: 0.47

Phenotypes
ARVC

Publications

• 33831308

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Association with deafness: MODERATE, two multiplex families with missense variants.

Association with muscular dystrophy LIMITED to MODERATE:
PMID: 21391237 (2011): Different variants reported in 2 adults with EDMD-related myopathy. Ile91Val present in gnomad, 20 hets. Other variant, Glu85Lys, presented in gnomad (1 het)

PMID: 30311943 (2019): 1 EDMD family reported with the same Glu85Lys variant. Muscle disease suspected at age of 17 in one family member.

Created: 12 Aug 2022, 1:14 a.m. | Last Modified: 12 Aug 2022, 1:14 a.m.

Panel Version: 0.142

DEFINITIVE by ClinGen for ARVC, multiple families reported, functional data. Common founder variant p.Ser358Leu.

Created: 3 Oct 2020, 9:34 a.m. | Last Modified: 12 Aug 2022, 1:14 a.m.

Panel Version: 0.142

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Arrhythmogenic right ventricular dysplasia 5, MIM# 604400; Auditory neuropathy, autosomal dominant 3, MIM# 619832; Emery-Dreifuss muscular dystrophy 7 (MIM#614302)

Publications

• 18313022
• 21214875
• 23812740
• 22725725
• 24598986
• 29980933
• 34050020
• 21391237
• 30311943

I don't know

Definitive for ARVC by ClinGen working group

p.(Ser358Leu) is known as the "Newfoundland" founder variant

From ClinGen:
At least 9 variants (mostly missense) have been reported. However, the pathogenicity of most of the variants is unknown. The majority of genetic evidence comes from case-level data and segregation data for one founder variant, p.(Ser358Leu), which has been reported in more than 20 families with ARVC and occurred 1x de novo (PMID:18313022;21214875;23812740; 22725725;24598986).

*no reports for isolated DCM
Sources: Literature

Created: 5 Aug 2020, 2:01 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Arrhythmogenic right ventricular dysplasia 5 (MIM# 604400)

Publications

• 18313022
• 21214875
• 23812740
• 22725725
• 24598986