Variant summary: The TMEM43 c.1073C>T (p.Ser358Leu) variant involves the alteration of a conserved nucleotide and is located in third transmembrane domain of the protein (Christensen_2011). 4/4 in silico tools predict a damaging outcome for this variant. Functional studies have shown that the S358L mutant reduces conduction velocity, increases the stiffness cell nuclei and alters the gap junction function (Siragam_PLoS One_2014 and Milting_Eur Heart J_2015). This variant was absent in 123942 control chromosomes. This variant has been widely reported as a founder mutation in Newfoundland. From a study of 15 families from Newfoundland, median age to develop an ARVD associated phenotype was 32 years for males and 44 years for females, with 100% of males and females penetrant by 63 and 76 years, respectively (Milting_Eur Heart J_2015). Haplotype analysis revealed an estimated age of 13001500 years for the mutation, which proves the European origin of the Newfoundland mutation (Milting_Eur Heart J_2015). Interestingly, this variant was also found as a confirmed de novo variant in an ARVC patient from New Zealand. Haplotype analysis revealed that the mutation occurred on a different haplotype in the patient than in the patients from Newfoundland (Baskin_HG_2013). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_024334.3(TMEM43):c.1073C>T (p.Ser358Leu)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(19)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
19
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024334.3(TMEM43):c.1073C>T (p.Ser358Leu)
Variation ID: 734 Accession: VCV000000734.50
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p25.1 3: 14141665 (GRCh38) [ NCBI UCSC ] 3: 14183165 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 24, 2015 Oct 20, 2024 Jan 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024334.3:c.1073C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077310.1:p.Ser358Leu missense NC_000003.12:g.14141665C>T NC_000003.11:g.14183165C>T NG_008975.1:g.21726C>T LRG_435:g.21726C>T LRG_435t1:c.1073C>T LRG_435p1:p.Ser358Leu Q9BTV4:p.Ser358Leu - Protein change
- S358L
- Other names
-
p.S358L:TCG>TTG
- Canonical SPDI
- NC_000003.12:14141664:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TMEM43 | No evidence available | No evidence available |
GRCh38 GRCh37 |
952 | 996 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 17, 2024 | RCV000000770.20 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2022 | RCV000183944.26 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 25, 2016 | RCV000588763.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 15, 2023 | RCV000621202.6 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 15, 2015 | RCV000039375.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 21, 2023 | RCV001181315.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 7, 2019 | RCV001254741.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 26, 2021 | RCV001375655.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 15, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000207271.3
First in ClinVar: Feb 06, 2015 Last updated: Feb 24, 2015 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Jul 25, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial isolated arrhythmogenic right ventricular dysplasia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699486.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The TMEM43 c.1073C>T (p.Ser358Leu) variant involves the alteration of a conserved nucleotide and is located in third transmembrane domain of the protein (Christensen_2011). … (more)
Variant summary: The TMEM43 c.1073C>T (p.Ser358Leu) variant involves the alteration of a conserved nucleotide and is located in third transmembrane domain of the protein (Christensen_2011). 4/4 in silico tools predict a damaging outcome for this variant. Functional studies have shown that the S358L mutant reduces conduction velocity, increases the stiffness cell nuclei and alters the gap junction function (Siragam_PLoS One_2014 and Milting_Eur Heart J_2015). This variant was absent in 123942 control chromosomes. This variant has been widely reported as a founder mutation in Newfoundland. From a study of 15 families from Newfoundland, median age to develop an ARVD associated phenotype was 32 years for males and 44 years for females, with 100% of males and females penetrant by 63 and 76 years, respectively (Milting_Eur Heart J_2015). Haplotype analysis revealed an estimated age of 13001500 years for the mutation, which proves the European origin of the Newfoundland mutation (Milting_Eur Heart J_2015). Interestingly, this variant was also found as a confirmed de novo variant in an ARVC patient from New Zealand. Haplotype analysis revealed that the mutation occurred on a different haplotype in the patient than in the patients from Newfoundland (Baskin_HG_2013). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987538.1
First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019 |
|
|
|
Pathogenic
(Dec 01, 2018)
|
criteria provided, single submitter
Method: research
|
Arrhythmogenic right ventricular dysplasia 5
cardiomyopathy diagnosed at autopsy
(more...)
Affected status: yes
Allele origin:
unknown
|
Heart Center, Academic Medical Center Amsterdam
Accession: SCV000992155.1
First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019 |
|
|
|
Pathogenic
(Dec 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001346435.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces serine with leucine at codon 358 in the third transmembrane domain of the TMEM43 protein. Computational prediction is inconclusive regarding the … (more)
This missense variant replaces serine with leucine at codon 358 in the third transmembrane domain of the TMEM43 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant affects localization of proteins involved in conduction, alter gap junction function and reduce conduction velocity in cardiac tissue (PMID: 25343256). This variant has been reported in numerous individuals affected with arrhythmogenic right ventricular cardiomyopathy and is particularly common in the Newfoundland population (PMID: 18313022, 22725725, 24598986, 26513349). This variant shows full penetrance and causes an extremely severe, lethal phenotype, especially in males (PMID: 18313022, 22725725). This variant has been shown to segregate with disease in up to 20 families (PMID: 18313022, 21214875, 24598986, 28491673). This variant has been identified to be de novo in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23812740). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jun 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002043562.3
First in ClinVar: Jan 01, 2022 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 5
Affected status: unknown
Allele origin:
maternal
|
KardioGenetik, Herz- und Diabeteszentrum NRW
Accession: SCV004363566.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jun 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 5
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004841606.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces serine with leucine at codon 358 in the third transmembrane domain of the TMEM43 protein. Computational prediction is inconclusive regarding the … (more)
This missense variant replaces serine with leucine at codon 358 in the third transmembrane domain of the TMEM43 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant affects localization of proteins involved in conduction, alter gap junction function and reduce conduction velocity in cardiac tissue (PMID: 25343256). This variant has been reported in numerous individuals affected with arrhythmogenic right ventricular cardiomyopathy and is particularly common in the Newfoundland population (PMID: 18313022, 22725725, 24598986, 26513349). This variant shows full penetrance and causes an extremely severe, lethal phenotype, especially in males (PMID: 18313022, 22725725). This variant has been shown to segregate with disease in up to 20 families (PMID: 18313022, 21214875, 24598986, 28491673). This variant has been identified to be de novo in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23812740). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002544770.16
First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024 |
Comment:
TMEM43: PS3, PM2, PS2:Moderate, PS4:Moderate
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Feb 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Primary dilated cardiomyopathy
Affected status: yes
Allele origin:
somatic
|
Loeys Lab, Universiteit Antwerpen
Accession: SCV001572583.1
First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021 |
Comment:
This sequence change results in a missense variant in the TMEM43 gene (p.(Ser358Leu)). This variant is absent from population databases such as GnomAD (PM2). The … (more)
This sequence change results in a missense variant in the TMEM43 gene (p.(Ser358Leu)). This variant is absent from population databases such as GnomAD (PM2). The variant has been described in literature before in association with ARVC and was identified as a founder mutation in the Newfoundland population. It has been detected in several unrelated individuals and has shown to segregate with ARVC within several families. In some ARVC individuals it occurred de novo (PMID: 19467449; PMID: 18313022; PMID: 21214875; PMID: 23812740; PMID: 22725725; PMID: 24598986) (PP1 strong; PM6). The variant affects a highly conserved nucleotide and is located in the third transmembrane domain of the protein (PMID: 2121487) (PM1). Prediction programs predict a pathogenic effect (PP3). Functional studies have shown that the variant results in a reduction of conduction velocity and alters the gap junction function (PMID: 25343256; PMID: 24598986)(PS3). It was reported as pathogenic by multiple reputable laboratories and databases (PP5). We identified this variant in a family with DCM, some members of the family carried an additional variant of unknown significance in the MYPN gene (c.59A>G). In conclusion this variant was classified as pathogenic according to ACMG-guidelines (PS3; PP1 strong; PM2; PM1; PM6; PP3; PP5). (less)
Number of individuals with the variant: 3
Indication for testing: Primary dilated cardiomyopathy
Family history: yes
Sex: male
Tissue: blood
Secondary finding: no
|
|
|
Pathogenic
(Mar 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000236436.15
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Identified as a founder mutation in the Newfoundland population associated with autosomal dominant arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5), which is fully penetrant and … (more)
Identified as a founder mutation in the Newfoundland population associated with autosomal dominant arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5), which is fully penetrant and results in a severe phenotype (Hodgkinson et al., 2013; Merner et al., 2008); Not observed in large population cohorts (gnomAD); Published transfection studies demonstrate that this variant likely affects localization and function of intercalated disc proteins, and cells expressing p.(S358L) showed slower and more irregular rhythm and reduced conduction velocity (Siragam et al., 2014); transgenic knock-in mice also partially reproduce features of ARVC/D including cardiac fibrosis (Zheng et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29980933, 23671136, 26513349, 28491673, 24598986, 22458570, 22725725, 23810883, 26966288, 18313022, 27617087, 28960618, 29997227, 21214875, 24125834, 20010364, 30700137, 30355260, 30409740, 31567019, 32120009, 31402444, 32858485, 32062046, 25343256, 23812740, 34691145) (less)
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|
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Pathogenic
(Dec 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 5
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000764088.7
First in ClinVar: May 29, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 358 of the TMEM43 protein (p.Ser358Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 358 of the TMEM43 protein (p.Ser358Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 18313022, 21214875, 22725725, 23810883, 23812740, 24598986). In at least one individual the variant was observed to be de novo. It is commonly reported in individuals of Newfoundland ancestry (PMID: 18313022, 21214875, 22725725, 23810883, 23812740, 24598986). ClinVar contains an entry for this variant (Variation ID: 734). 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 not expected to disrupt TMEM43 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TMEM43 function (PMID: 25343256). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jun 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000736856.6
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.S358L pathogenic mutation (also known as c.1073C>T), located in coding exon 12 of the TMEM43 gene, results from a C to T substitution at … (more)
The p.S358L pathogenic mutation (also known as c.1073C>T), located in coding exon 12 of the TMEM43 gene, results from a C to T substitution at nucleotide position 1073. The serine at codon 358 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with known or suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), has segregated with disease in multiple families, and has been reported as a Newfoundland founder mutation as well as having been reported to occur de novo. Studies of some families indicate this alteration is highly penetrant with increased risk of arrhythmia and earlier onset disease in males (Merner ND et al. Am J Hum Genet. 2008;82:809-21; Hodgkinson K et al. Genet Med. 2009;11:859-65; Christensen AH et al. Clin Genet. 2011;80:256-64; Baskin B et al. Hum Genet. 2013;132:1245-52; Bhonsale A et al. Circ Arrhythm Electrophysiol. 2013;6:569-78; Hodgkinson KA et al. Clin Genet. 2013;83:321-31; Perrin MJ et al. J Am Coll Cardiol. 2013;62:1772-9; Milting H et al. Eur Heart J. 2015;36:872-81). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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|
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Pathogenic
(Dec 03, 2010)
|
no assertion criteria provided
Method: clinical testing
|
Not provided
Affected status: not provided
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280493.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. This variant was found in a large kindred in Newfoundland (Merner et al 2008) with strong segregation data supporting it's pathogenicity. In that study the variant was not observed in 208 control individuals. In silico analysis with Polyphen-2 predicts the variant to be probably damaging. The Serene at codon 358 is completely conserved across species. Merner et al reported that in their kindred of 257 affected individuals there was age-dependent but complete penetrance with a severe phenotype. The phenotype was modified by gender, with a median life expectancy of 41 years in males and 71 years in females. Heart failure was a late manifestation. (less)
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|
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Pathogenic
(Nov 01, 2013)
|
no assertion criteria provided
Method: literature only
|
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020920.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 30, 2018 |
Comment on evidence:
In affected individuals with arrhythmogenic right ventricular dysplasia (ARVD5; 604400) from 15 unrelated Newfoundland families, Merner et al. (2008) identified heterozygosity for a 1073C-T transition … (more)
In affected individuals with arrhythmogenic right ventricular dysplasia (ARVD5; 604400) from 15 unrelated Newfoundland families, Merner et al. (2008) identified heterozygosity for a 1073C-T transition in the TMEM43 gene, resulting in a ser358-to-leu (S358L) substitution at a highly conserved residue within the third predicted transmembrane domain. The mutation was not found in 47 spouses or 161 controls. Of 61 'unaffected' individuals who carried the mutation, 35 (57%) were found to have clinical signs of ARVD on subsequent testing, and penetrance was 100% in mutation-positive males and females at ages 63 and 76 years, respectively. In a Danish woman and her affected mother with ARVD, Christensen et al. (2011) identified heterozygosity for the S358L mutation in the TMEM43 gene. The mutation was not found in the proband's unaffected sister or in 650 ethnically matched controls. The proband became symptomatic at 49 years of age and was diagnosed based on the presence of ventricular tachycardia (VT), T-wave inversion in leads V1 to V5, late potentials on signal-averaged ECG, dilated right ventricle, and fibrofatty infiltrations on endomyocardial biopsy. Her mother, who was subsequently diagnosed at 70 years of age, had similar findings except that biopsy showed fatty infiltrations but no fibrosis. Both patients had normal left ventricular diameter and function. Immunostaining of patient myocardium for TMEM43 showed localization to the sarcolemma, with reduced signal in the patients compared to controls; similar immunostaining for plakoglobin (JUP; 173325) also showed reduced signal, suggesting that TMEM43-associated ARVD shares a final common pathway with desmosome-associated ARVD. Baskin et al. (2013) identified the TMEM43 S358L 'Newfoundland' mutation in 6 patients, including a 43-year-old New Zealand man who was not of Newfoundland descent. The mutation, which occurred de novo in the New Zealand patient, arose on a different haplotype from that of the patients from Newfoundland, suggesting that S358 might represent a hotspot for sequence alteration. (less)
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|
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Pathogenic
(Apr 04, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000063059.6
First in ClinVar: May 03, 2013 Last updated: Feb 24, 2015 |
Comment:
The p.Ser358Leu variant in TMEM43 has been reported in >20 families with ARVC (a t least 15 from Newfoundland), including 1 de novo occurrence and … (more)
The p.Ser358Leu variant in TMEM43 has been reported in >20 families with ARVC (a t least 15 from Newfoundland), including 1 de novo occurrence and segregated wit h disease in >20 affected relatives from these families (Merner 2008, Christense n 2011, Baskin 2013, Hodgkinson 2013, Milting 2014). It was absent from large po pulation studies. In summary, this variant meets criteria to be classified as pa thogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PS4, PP1_Strong , PM2, PM6, PP3. (less)
Number of individuals with the variant: 27
|
|
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Pathogenic
(Aug 07, 2019)
|
no assertion criteria provided
Method: research
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV001430826.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
Comment:
This variant has been identified in 1 HCM proband of Southern Asian descent as part of our research program. For further information please feel free … (more)
This variant has been identified in 1 HCM proband of Southern Asian descent as part of our research program. For further information please feel free to contact us. (less)
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not provided
(-)
|
no classification provided
Method: literature only
|
Arrhythmogenic right ventricular dysplasia 5
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV001983380.2
First in ClinVar: Oct 30, 2021 Last updated: Oct 01, 2022 |
|
|
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Pathogenic
(Jun 26, 2016)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000740428 appears to be redundant with SCV000987538.
(less)
Notes: SCV000740428 appears to
(...more)
Source: NCBI
|
not provided
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740428.1
First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018 |
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Comment:
Comment on condition
cardiomyopathy diagnosed at autopsy after sudden death
Comment:
This missense variant replaces serine with leucine at codon 358 in the third transmembrane domain of the TMEM43 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant affects localization of proteins involved in conduction, alter gap junction function and reduce conduction velocity in cardiac tissue (PMID: 25343256). This variant has been reported in numerous individuals affected with arrhythmogenic right ventricular cardiomyopathy and is particularly common in the Newfoundland population (PMID: 18313022, 22725725, 24598986, 26513349). This variant shows full penetrance and causes an extremely severe, lethal phenotype, especially in males (PMID: 18313022, 22725725). This variant has been shown to segregate with disease in up to 20 families (PMID: 18313022, 21214875, 24598986, 28491673). This variant has been identified to be de novo in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23812740). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This missense variant replaces serine with leucine at codon 358 in the third transmembrane domain of the TMEM43 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant affects localization of proteins involved in conduction, alter gap junction function and reduce conduction velocity in cardiac tissue (PMID: 25343256). This variant has been reported in numerous individuals affected with arrhythmogenic right ventricular cardiomyopathy and is particularly common in the Newfoundland population (PMID: 18313022, 22725725, 24598986, 26513349). This variant shows full penetrance and causes an extremely severe, lethal phenotype, especially in males (PMID: 18313022, 22725725). This variant has been shown to segregate with disease in up to 20 families (PMID: 18313022, 21214875, 24598986, 28491673). This variant has been identified to be de novo in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23812740). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
TMEM43: PS3, PM2, PS2:Moderate, PS4:Moderate
Comment:
This sequence change results in a missense variant in the TMEM43 gene (p.(Ser358Leu)). This variant is absent from population databases such as GnomAD (PM2). The variant has been described in literature before in association with ARVC and was identified as a founder mutation in the Newfoundland population. It has been detected in several unrelated individuals and has shown to segregate with ARVC within several families. In some ARVC individuals it occurred de novo (PMID: 19467449; PMID: 18313022; PMID: 21214875; PMID: 23812740; PMID: 22725725; PMID: 24598986) (PP1 strong; PM6). The variant affects a highly conserved nucleotide and is located in the third transmembrane domain of the protein (PMID: 2121487) (PM1). Prediction programs predict a pathogenic effect (PP3). Functional studies have shown that the variant results in a reduction of conduction velocity and alters the gap junction function (PMID: 25343256; PMID: 24598986)(PS3). It was reported as pathogenic by multiple reputable laboratories and databases (PP5). We identified this variant in a family with DCM, some members of the family carried an additional variant of unknown significance in the MYPN gene (c.59A>G). In conclusion this variant was classified as pathogenic according to ACMG-guidelines (PS3; PP1 strong; PM2; PM1; PM6; PP3; PP5).
Comment:
Identified as a founder mutation in the Newfoundland population associated with autosomal dominant arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5), which is fully penetrant and results in a severe phenotype (Hodgkinson et al., 2013; Merner et al., 2008); Not observed in large population cohorts (gnomAD); Published transfection studies demonstrate that this variant likely affects localization and function of intercalated disc proteins, and cells expressing p.(S358L) showed slower and more irregular rhythm and reduced conduction velocity (Siragam et al., 2014); transgenic knock-in mice also partially reproduce features of ARVC/D including cardiac fibrosis (Zheng et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29980933, 23671136, 26513349, 28491673, 24598986, 22458570, 22725725, 23810883, 26966288, 18313022, 27617087, 28960618, 29997227, 21214875, 24125834, 20010364, 30700137, 30355260, 30409740, 31567019, 32120009, 31402444, 32858485, 32062046, 25343256, 23812740, 34691145)
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 358 of the TMEM43 protein (p.Ser358Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 18313022, 21214875, 22725725, 23810883, 23812740, 24598986). In at least one individual the variant was observed to be de novo. It is commonly reported in individuals of Newfoundland ancestry (PMID: 18313022, 21214875, 22725725, 23810883, 23812740, 24598986). ClinVar contains an entry for this variant (Variation ID: 734). 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 not expected to disrupt TMEM43 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TMEM43 function (PMID: 25343256). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.S358L pathogenic mutation (also known as c.1073C>T), located in coding exon 12 of the TMEM43 gene, results from a C to T substitution at nucleotide position 1073. The serine at codon 358 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with known or suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), has segregated with disease in multiple families, and has been reported as a Newfoundland founder mutation as well as having been reported to occur de novo. Studies of some families indicate this alteration is highly penetrant with increased risk of arrhythmia and earlier onset disease in males (Merner ND et al. Am J Hum Genet. 2008;82:809-21; Hodgkinson K et al. Genet Med. 2009;11:859-65; Christensen AH et al. Clin Genet. 2011;80:256-64; Baskin B et al. Hum Genet. 2013;132:1245-52; Bhonsale A et al. Circ Arrhythm Electrophysiol. 2013;6:569-78; Hodgkinson KA et al. Clin Genet. 2013;83:321-31; Perrin MJ et al. J Am Coll Cardiol. 2013;62:1772-9; Milting H et al. Eur Heart J. 2015;36:872-81). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. This variant was found in a large kindred in Newfoundland (Merner et al 2008) with strong segregation data supporting it's pathogenicity. In that study the variant was not observed in 208 control individuals. In silico analysis with Polyphen-2 predicts the variant to be probably damaging. The Serene at codon 358 is completely conserved across species. Merner et al reported that in their kindred of 257 affected individuals there was age-dependent but complete penetrance with a severe phenotype. The phenotype was modified by gender, with a median life expectancy of 41 years in males and 71 years in females. Heart failure was a late manifestation.
Comment:
The p.Ser358Leu variant in TMEM43 has been reported in >20 families with ARVC (a t least 15 from Newfoundland), including 1 de novo occurrence and segregated wit h disease in >20 affected relatives from these families (Merner 2008, Christense n 2011, Baskin 2013, Hodgkinson 2013, Milting 2014). It was absent from large po pulation studies. In summary, this variant meets criteria to be classified as pa thogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PS4, PP1_Strong , PM2, PM6, PP3.
Comment:
This variant has been identified in 1 HCM proband of Southern Asian descent as part of our research program. For further information please feel free to contact us.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: The TMEM43 c.1073C>T (p.Ser358Leu) variant involves the alteration of a conserved nucleotide and is located in third transmembrane domain of the protein (Christensen_2011). 4/4 in silico tools predict a damaging outcome for this variant. Functional studies have shown that the S358L mutant reduces conduction velocity, increases the stiffness cell nuclei and alters the gap junction function (Siragam_PLoS One_2014 and Milting_Eur Heart J_2015). This variant was absent in 123942 control chromosomes. This variant has been widely reported as a founder mutation in Newfoundland. From a study of 15 families from Newfoundland, median age to develop an ARVD associated phenotype was 32 years for males and 44 years for females, with 100% of males and females penetrant by 63 and 76 years, respectively (Milting_Eur Heart J_2015). Haplotype analysis revealed an estimated age of 13001500 years for the mutation, which proves the European origin of the Newfoundland mutation (Milting_Eur Heart J_2015). Interestingly, this variant was also found as a confirmed de novo variant in an ARVC patient from New Zealand. Haplotype analysis revealed that the mutation occurred on a different haplotype in the patient than in the patients from Newfoundland (Baskin_HG_2013). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Comment on condition
cardiomyopathy diagnosed at autopsy after sudden death
Comment:
This missense variant replaces serine with leucine at codon 358 in the third transmembrane domain of the TMEM43 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant affects localization of proteins involved in conduction, alter gap junction function and reduce conduction velocity in cardiac tissue (PMID: 25343256). This variant has been reported in numerous individuals affected with arrhythmogenic right ventricular cardiomyopathy and is particularly common in the Newfoundland population (PMID: 18313022, 22725725, 24598986, 26513349). This variant shows full penetrance and causes an extremely severe, lethal phenotype, especially in males (PMID: 18313022, 22725725). This variant has been shown to segregate with disease in up to 20 families (PMID: 18313022, 21214875, 24598986, 28491673). This variant has been identified to be de novo in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23812740). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This missense variant replaces serine with leucine at codon 358 in the third transmembrane domain of the TMEM43 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant affects localization of proteins involved in conduction, alter gap junction function and reduce conduction velocity in cardiac tissue (PMID: 25343256). This variant has been reported in numerous individuals affected with arrhythmogenic right ventricular cardiomyopathy and is particularly common in the Newfoundland population (PMID: 18313022, 22725725, 24598986, 26513349). This variant shows full penetrance and causes an extremely severe, lethal phenotype, especially in males (PMID: 18313022, 22725725). This variant has been shown to segregate with disease in up to 20 families (PMID: 18313022, 21214875, 24598986, 28491673). This variant has been identified to be de novo in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23812740). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
TMEM43: PS3, PM2, PS2:Moderate, PS4:Moderate
Comment:
This sequence change results in a missense variant in the TMEM43 gene (p.(Ser358Leu)). This variant is absent from population databases such as GnomAD (PM2). The variant has been described in literature before in association with ARVC and was identified as a founder mutation in the Newfoundland population. It has been detected in several unrelated individuals and has shown to segregate with ARVC within several families. In some ARVC individuals it occurred de novo (PMID: 19467449; PMID: 18313022; PMID: 21214875; PMID: 23812740; PMID: 22725725; PMID: 24598986) (PP1 strong; PM6). The variant affects a highly conserved nucleotide and is located in the third transmembrane domain of the protein (PMID: 2121487) (PM1). Prediction programs predict a pathogenic effect (PP3). Functional studies have shown that the variant results in a reduction of conduction velocity and alters the gap junction function (PMID: 25343256; PMID: 24598986)(PS3). It was reported as pathogenic by multiple reputable laboratories and databases (PP5). We identified this variant in a family with DCM, some members of the family carried an additional variant of unknown significance in the MYPN gene (c.59A>G). In conclusion this variant was classified as pathogenic according to ACMG-guidelines (PS3; PP1 strong; PM2; PM1; PM6; PP3; PP5).
Comment:
Identified as a founder mutation in the Newfoundland population associated with autosomal dominant arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5), which is fully penetrant and results in a severe phenotype (Hodgkinson et al., 2013; Merner et al., 2008); Not observed in large population cohorts (gnomAD); Published transfection studies demonstrate that this variant likely affects localization and function of intercalated disc proteins, and cells expressing p.(S358L) showed slower and more irregular rhythm and reduced conduction velocity (Siragam et al., 2014); transgenic knock-in mice also partially reproduce features of ARVC/D including cardiac fibrosis (Zheng et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29980933, 23671136, 26513349, 28491673, 24598986, 22458570, 22725725, 23810883, 26966288, 18313022, 27617087, 28960618, 29997227, 21214875, 24125834, 20010364, 30700137, 30355260, 30409740, 31567019, 32120009, 31402444, 32858485, 32062046, 25343256, 23812740, 34691145)
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 358 of the TMEM43 protein (p.Ser358Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 18313022, 21214875, 22725725, 23810883, 23812740, 24598986). In at least one individual the variant was observed to be de novo. It is commonly reported in individuals of Newfoundland ancestry (PMID: 18313022, 21214875, 22725725, 23810883, 23812740, 24598986). ClinVar contains an entry for this variant (Variation ID: 734). 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 not expected to disrupt TMEM43 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TMEM43 function (PMID: 25343256). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.S358L pathogenic mutation (also known as c.1073C>T), located in coding exon 12 of the TMEM43 gene, results from a C to T substitution at nucleotide position 1073. The serine at codon 358 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with known or suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), has segregated with disease in multiple families, and has been reported as a Newfoundland founder mutation as well as having been reported to occur de novo. Studies of some families indicate this alteration is highly penetrant with increased risk of arrhythmia and earlier onset disease in males (Merner ND et al. Am J Hum Genet. 2008;82:809-21; Hodgkinson K et al. Genet Med. 2009;11:859-65; Christensen AH et al. Clin Genet. 2011;80:256-64; Baskin B et al. Hum Genet. 2013;132:1245-52; Bhonsale A et al. Circ Arrhythm Electrophysiol. 2013;6:569-78; Hodgkinson KA et al. Clin Genet. 2013;83:321-31; Perrin MJ et al. J Am Coll Cardiol. 2013;62:1772-9; Milting H et al. Eur Heart J. 2015;36:872-81). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. This variant was found in a large kindred in Newfoundland (Merner et al 2008) with strong segregation data supporting it's pathogenicity. In that study the variant was not observed in 208 control individuals. In silico analysis with Polyphen-2 predicts the variant to be probably damaging. The Serene at codon 358 is completely conserved across species. Merner et al reported that in their kindred of 257 affected individuals there was age-dependent but complete penetrance with a severe phenotype. The phenotype was modified by gender, with a median life expectancy of 41 years in males and 71 years in females. Heart failure was a late manifestation.
Comment:
The p.Ser358Leu variant in TMEM43 has been reported in >20 families with ARVC (a t least 15 from Newfoundland), including 1 de novo occurrence and segregated wit h disease in >20 affected relatives from these families (Merner 2008, Christense n 2011, Baskin 2013, Hodgkinson 2013, Milting 2014). It was absent from large po pulation studies. In summary, this variant meets criteria to be classified as pa thogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PS4, PP1_Strong , PM2, PM6, PP3.
Comment:
This variant has been identified in 1 HCM proband of Southern Asian descent as part of our research program. For further information please feel free to contact us.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy. | Miles C | Circulation | 2019 | PMID: 30700137 |
| TMEM43-S358L mutation enhances NF-κB-TGFβ signal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Zheng G | Protein & cell | 2019 | PMID: 29980933 |
| Luma is not essential for murine cardiac development and function. | Stroud MJ | Cardiovascular research | 2018 | PMID: 29040414 |
| Failure of ICD therapy in lethal arrhythmogenic right ventricular cardiomyopathy type 5 caused by the TMEM43 p.Ser358Leu mutation. | Aalbæk Kjærgaard K | HeartRhythm case reports | 2016 | PMID: 28491673 |
| Perceived economic burden associated with an inherited cardiac condition: a qualitative inquiry with families affected by arrhythmogenic right ventricular cardiomyopathy. | Etchegary H | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26513349 |
| The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus. | Milting H | European heart journal | 2015 | PMID: 24598986 |
| TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. | Siragam V | PloS one | 2014 | PMID: 25343256 |
| Correlation of ventricular arrhythmias with genotype in arrhythmogenic right ventricular cardiomyopathy. | Bao J | Circulation. Cardiovascular genetics | 2013 | PMID: 24125834 |
| TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations. | Baskin B | Human genetics | 2013 | PMID: 23812740 |
| Exercise testing in asymptomatic gene carriers exposes a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy. | Perrin MJ | Journal of the American College of Cardiology | 2013 | PMID: 23810883 |
| Risk stratification in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. | Bhonsale A | Circulation. Arrhythmia and electrophysiology | 2013 | PMID: 23671136 |
| The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. | Hodgkinson KA | Clinical genetics | 2013 | PMID: 22725725 |
| Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy. | Rajkumar R | BMC medical genetics | 2012 | PMID: 22458570 |
| Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy. | Christensen AH | Clinical genetics | 2011 | PMID: 21214875 |
| Translation of research discoveries to clinical care in arrhythmogenic right ventricular cardiomyopathy in Newfoundland and Labrador: lessons for health policy in genetic disease. | Hodgkinson K | Genetics in medicine : official journal of the American College of Medical Genetics | 2009 | PMID: 20010364 |
| Sarcomere mutations in cardiogenesis and ventricular noncompaction. | McNally E | Trends in cardiovascular medicine | 2009 | PMID: 19467449 |
| Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. | Merner ND | American journal of human genetics | 2008 | PMID: 18313022 |
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Text-mined citations for rs63750743 ...
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Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.