chr3-14141665-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_024334.3(TMEM43):c.1073C>T(p.Ser358Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S358S) has been classified as Likely benign.
Frequency
Consequence
NM_024334.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TMEM43 | NM_024334.3 | c.1073C>T | p.Ser358Leu | missense_variant | Exon 12 of 12 | ENST00000306077.5 | NP_077310.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TMEM43 | ENST00000306077.5 | c.1073C>T | p.Ser358Leu | missense_variant | Exon 12 of 12 | 1 | NM_024334.3 | ENSP00000303992.5 | ||
| ENSG00000268279 | ENST00000608606.1 | n.235+2368C>T | intron_variant | Intron 3 of 4 | 5 | ENSP00000476275.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 5 Pathogenic:7Other:1
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The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. Premature termination of the protein is a common disease-causing mechanism for this gene. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000734 /PMID: 18313022). The variant has been previously reported as de novo in a similarly affected individual (PMID: 23812740). A different missense change at the same codon (p.Ser358Pro) has been reported to be associated with TMEM43 related disorder (ClinVar ID: VCV000924715). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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The missense variant c.1073C>Tp.Ser358Leu in TMEM43 gene has been observed in heterozygous state in multiple individuals with arrhythmogenic right ventricular cardiomyopathy ARVC Milting et. al., 2015; Baskin et. al., 2013. In at least one individual the variant was observed to be de novo. It is commonly reported in individuals of Newfoundland ancestry Milting et. al., 2015; Baskin et. al., 2013. Experimental studies have shown that this missense change affects TMEM43 function Siragam et. al., 2014. The observed variant is absent in gnomAD exomes database. This variant has been submitted to the ClinVar database as Pathogenic multiple submitters. Multiple lines of computational evidence Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing predict a damaging effect on protein structure and function for this variant. The amino acid change p.Ser358Leu in TMEM43 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 358 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. The observed variant has also been reported previously in affected sibling. -
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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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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. -
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not provided Pathogenic:4
TMEM43: PS3, PM2, PS2:Moderate, PS4:Moderate -
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. -
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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) -
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:3
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. -
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Cardiomyopathy Pathogenic:2
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. -
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Primary dilated cardiomyopathy Pathogenic:1
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). -
Hypertrophic cardiomyopathy Pathogenic:1
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. -
Cardiovascular phenotype Pathogenic:1
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. -
Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at