NM_024334.3(TMEM43):c.1073C>T (p.Ser358Leu) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Apr 1, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000183944.20

Allele description

NM_024334.3(TMEM43):c.1073C>T (p.Ser358Leu)

Gene:

TMEM43:transmembrane protein 43 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.1

Genomic location:

Preferred name:

NM_024334.3(TMEM43):c.1073C>T (p.Ser358Leu)

Other names:

p.S358L:TCG>TTG

HGVS:

NC_000003.12:g.14141665C>T
NG_008975.1:g.21726C>T
NM_024334.3:c.1073C>TMANE SELECT
NP_077310.1:p.Ser358Leu
NP_077310.1:p.Ser358Leu
LRG_435t1:c.1073C>T
LRG_435:g.21726C>T
LRG_435p1:p.Ser358Leu
NC_000003.11:g.14183165C>T
NM_024334.2:c.1073C>T
Q9BTV4:p.Ser358Leu
c.1073C>T
p.S358L

Protein change:

S358L; SER358LEU

Links:

UniProtKB: Q9BTV4#VAR_044438; OMIM: 612048.0001; dbSNP: rs63750743

NCBI 1000 Genomes Browser:

rs63750743

Molecular consequence:

NM_024334.3:c.1073C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000236436	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 29, 2022)	germline	clinical testing	Citation Link,
SCV000280493	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (Dec 3, 2010)	germline	clinical testing
SCV002544770	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Apr 1, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000236436

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 29, 2022)

germline

clinical testing

Citation Link,

SCV000280493

Stanford Center for Inherited Cardiovascular Disease, Stanford University

no assertion criteria provided

Pathogenic
(Dec 3, 2010)

germline

clinical testing

SCV002544770

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Apr 1, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000236436.15

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280493.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000740428.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV002544770.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

TMEM43: PS3, PM2, PS2:Moderate, PS4:Moderate

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000740428	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	flagged submission Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV000740428 appears to be redundant with SCV000987538. (ACMG Guidelines, 2015)	Pathogenic (Jun 26, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000740428

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

flagged submission

Reason: This record appears to be redundant with a more recent record from the same submitter.

Notes: SCV000740428 appears to be redundant with SCV000987538.

(ACMG Guidelines, 2015)

Pathogenic
(Jun 26, 2016)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: May 7, 2024

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