VCV000008293.66 - ClinVar

NM_033337.3(CAV3):c.233C>T (p.Thr78Met)

Germline

Classification

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.

(25)

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.

Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(9); Likely benign(6)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_033337.3(CAV3):c.233C>T (p.Thr78Met)

Variation ID: 8293 Accession: VCV000008293.66

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.3 3: 8745644 (GRCh38) [ NCBI UCSC ] 3: 8787330 (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	Apr 4, 2013	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_033337.3:c.233C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_203123.1:p.Thr78Met	missense
NM_001234.5:c.233C>T	NP_001225.1:p.Thr78Met	missense
NC_000003.12:g.8745644C>T
NC_000003.11:g.8787330C>T
NG_008797.2:g.16835C>T
LRG_329:g.16835C>T
LRG_329t1:c.233C>T	LRG_329p1:p.Thr78Met
	P56539:p.Thr78Met

... more HGVS ... less HGVS

Protein change

T78M

Other names

p.T78M:ACG>ATG

Canonical SPDI

NC_000003.12:8745643:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

unknown functional consequence

Global minor allele frequency (GMAF) Help The 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.

0.00200 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00172

1000 Genomes Project 0.00200

Trans-Omics for Precision Medicine (TOPMed) 0.00293

The Genome Aggregation Database (gnomAD) 0.00317

Links

dbSNP: rs72546668 ClinGen: CA119455 Leiden Muscular Dystrophy (CAV3): CAV3_00030 UniProtKB: P56539#VAR_043695 OMIM: 601253.0018 VarSome

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
Gene	OMIM	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.
CAV3		-	-	GRCh38 GRCh37	102	445
OXTR		-	-	GRCh38 GRCh37	34	376

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.
Long QT syndrome 2/9, digenic	Pathogenic (1)	no assertion criteria provided	Feb 1, 2007	RCV000008791.12
Long QT syndrome 9	Uncertain significance (2)	criteria provided, single submitter	Nov 21, 2018	RCV000008790.13
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000024406.49
not specified	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Apr 27, 2019	RCV000039801.30
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Feb 28, 2019	RCV000242756.12
Long QT syndrome	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000168328.23
Long QT syndrome 1	Likely benign (1)	criteria provided, single submitter	May 28, 2019	RCV000987088.9
Cardiomyopathy	Benign (2)	criteria provided, multiple submitters, no conflicts	Jun 5, 2018	RCV000769173.12
CAV3-related disorder	Likely benign (1)	no assertion criteria provided	Feb 19, 2019	RCV003924817.2
Caveolinopathy	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001144019.12
Hypertrophic cardiomyopathy	Uncertain significance (1)	no assertion criteria provided	-	RCV004764897.1
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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.
Likely benign (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	isolated hyperkalemia Long QT syndrome Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000050767.2 First in ClinVar: Jun 04, 2015 Last updated: Sep 14, 2015 Comments (2): The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less) Medical sequencing	Number of individuals with the variant: 5
Benign (Feb 17, 2015)	criteria provided, single submitter (Variant Classification) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000188740.3 First in ClinVar: Sep 07, 2014 Last updated: Apr 14, 2018	Number of individuals with the variant: 1
Benign (Aug 16, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000740556.1 First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018
Likely benign (Jul 15, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000114283.8 First in ClinVar: Jan 22, 2014 Last updated: Apr 14, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAV3 Number of individuals with the variant: 9 Sex: mixed
Uncertain significance (Nov 21, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Long QT syndrome 9 Affected status: unknown Allele origin: unknown	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000883139.1 First in ClinVar: Sep 28, 2018 Last updated: Sep 28, 2018
Uncertain significance (Apr 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000930434.1 First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019	Observation 1: Geographic origin: Iran Observation 2: Geographic origin: Iran
Likely benign (Aug 12, 2015)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000063490.5 First in ClinVar: May 03, 2013 Last updated: Dec 06, 2016	Publications: PubMed (4) PubMed: 17060380‚ 18253147‚ 17275750‚ 16770780 Comment: p.Thr78Met in exon 2 of CAV3: This variant has been reported in 1 individual wit h idiopathic hyper-CK-emia, 3 individuals with LQTS (one of whom … (more) p.Thr78Met in exon 2 of CAV3: This variant has been reported in 1 individual wit h idiopathic hyper-CK-emia, 3 individuals with LQTS (one of whom had a second pa thogenic variant), 1 individual with DCM and limb-girdle muscular dystrophy (hom ozygous for this variant), and 1 infant with SIDS, and was not detected in >1500 control chromosomes (Reijneveld 2006, Vatta 2006, Cronk 2007, Traverso 2008). H owever, this variant is not expected to have clinical significance because it ha s been identified in 0.4% (276/66492) of European chromosomes and 0.46% (48/1037 6) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org/, dbSNP rs72546668). (less) Number of individuals with the variant: 15
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Long QT syndrome 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136286.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Caveolinopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001304593.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (6) PubMed: 22378279‚ 23465283‚ 16770780‚ 22595201‚ 22245016‚ 17060380 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Benign (Jun 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV000900548.2 First in ClinVar: May 06, 2019 Last updated: May 31, 2020
Benign (Aug 02, 2019)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602911.3 First in ClinVar: Dec 06, 2016 Last updated: Jan 26, 2021
Benign (Jul 13, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000167539.13 First in ClinVar: Jun 23, 2014 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 17275750, 24123366, 23640888, 18253147, 24070816, 24021552, 23465283, 22378279, 22245016, 22595201, 17060380, 26656175, 26159999, 27312022, 29367541, 28648120, … (more) This variant is associated with the following publications: (PMID: 17275750, 24123366, 23640888, 18253147, 24070816, 24021552, 23465283, 22378279, 22245016, 22595201, 17060380, 26656175, 26159999, 27312022, 29367541, 28648120, 28898996, 30986657, 28988457, 31019283, 31043699) (less)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Long QT syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000219015.11 First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024
Likely benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248495.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: CAV3: BS1 Number of individuals with the variant: 9
Benign (Aug 22, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699769.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (13) PubMed: 22584458‚ 18253147‚ 23640888‚ 24123366‚ 17060380‚ 22245016‚ 17275750‚ 22378279‚ 24021552‚ 24070816‚ 17210839‚ 24503780‚ 16770780 Comment: Variant Summary: CAV3 c.233C>T (p.T78M) affects a conserved nucleotide and 4/5 in-silico tools predict this variant to be damaging. The variant is located within the … (more) Variant Summary: CAV3 c.233C>T (p.T78M) affects a conserved nucleotide and 4/5 in-silico tools predict this variant to be damaging. The variant is located within the central hydrophobic transmembrane domain (amino acids 75106) of caveolin-3 and has previously been reported to be disease causing. In vitro functional studies have shown that T78M interacts with the cardiac sodium channel to promote increased persistent current. However, it may be meaningless to assess the effects that CAV3 mutations have on a single ion channel without being able to assess the effect on the action potential as a whole due to the complex regulatory nature of the different cardiac ion channels that localize within caveolae. Therefore, the finding that T78M CAV3 expressed heterologously in HEK293 cell lines stably expressing the most common (Q1077del) variant of SCN5A-encoded cardiac sodium channel can cause a five-fold increase in late sodium current should not be considered strong evidence for pathogenicity. Detection of CAV3 T78M in unrelated patients with various diseases has led to its repeated labeling as pathogenic in the literature. However, many of these patients had a co-occurrence that could explain most, if not all, of the presenting phenotype. Additionally, T78M was found in 379/124242 control chromosomes at a frequency of 0.0030505, which is more than 121 times the maximal expected frequency of a CAV3 pathogenic allele (0.000025), suggesting this variant is a benign polymorphism. Patient observations and limited in vitro characterization are not sufficient to conclude that CAV T78M is pathogenic. It is possible that CAV3 T78M may exert a pathogenic effect in association with other genetic factors, however in isolation, the evidence strongly supports a benign classification of this variant. Additionally, several reputable labs classify the variant as benign/likely benign. Taken together, this variant was classified as benign. (less)
Benign (Mar 22, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995704.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
Benign (Jun 12, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001143446.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (25) PubMed: 28898996‚ 19773168‚ 27312022‚ 26159999‚ 27600940‚ 25757662‚ 29501670‚ 27483260‚ 31043699‚ 30704477‚ 29396561‚ 28407228‚ 24021552‚ 23465283‚ 23640888‚ 24070816‚ 24123366‚ 16770780‚ 17060380‚ 17210839‚ 17275750‚ 18253147‚ 22245016‚ 22378279‚ 22595201
Uncertain significance (Jan 08, 2024)	criteria provided, single submitter (Dept of Medical Biology Variant Classification) Method: research	Long QT syndrome Affected status: yes Allele origin: maternal	Dept of Medical Biology, Uskudar University Accession: SCV004022049.2 First in ClinVar: Jul 29, 2023 Last updated: Jan 26, 2024	Comment: Criteria: PP2, PP3, BS1 Number of individuals with the variant: 2 Sex: mixed Ethnicity/Population group: Turkish Geographic origin: Turkey
Likely benign (Feb 28, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318969.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. (less)
Pathogenic (Feb 01, 2007)	no assertion criteria provided Method: literature only	LONG QT SYNDROME 9 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029000.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 28, 2018	Publications: PubMed (3) PubMed: 15580566‚ 17060380‚ 17275750 Comment on evidence: The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). In 3 unrelated individuals with long QT … (more) The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). In 3 unrelated individuals with long QT syndrome (LQT9; 611818), Vatta et al. (2006) identified heterozygosity for a 233C-T transition in the CAV3 gene, resulting in a thr78-to-met (T78M) substitution at a highly conserved residue. All 3 patients had a positive family history, but family members declined further genotyping. One patient had biallelic digenic mutations: she was a 14-year-old girl with nonexertional syncope and a 'seizure-like' presentation, who had U waves, sinus bradycardia, and a QTc of 405 ms on ECG, and was found to carry a A913V mutation in the LQT2-associated KCNH2 gene (152427.0024) as well as the T78M mutation. The other 2 patients, who were negative for mutations in other known LQTS genes, were an 8-year-old boy with nonexertional syncope and marked sinus bradycardia with a QTc of 433 ms and an asymptomatic 40-year-old male who had a QTc of 456 ms. The T78M mutation was not found in more than 1,000 control alleles. In frozen necropsy tissue from a 2-month-old black female infant who died of sudden infant death syndrome (SIDS; 272120), Cronk et al. (2007) identified the T78M mutation in the CAV3 gene. Voltage-clamp studies in HEK293 cells demonstrated that the mutant caused a 5-fold increase in late sodium current compared to wildtype. The mutation was not found in 400 reference alleles, of which 200 were ethnically matched. (less)
Pathogenic (Feb 01, 2007)	no assertion criteria provided Method: literature only	LONG QT SYNDROME 2/9, DIGENIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029001.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 28, 2018	Publications: PubMed (3) PubMed: 15580566‚ 17060380‚ 17275750 Comment on evidence: The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). In 3 unrelated individuals with long QT … (more) The numbering of this CAV3 mutation is based on the numbering system used by Fulizio et al. (2005). In 3 unrelated individuals with long QT syndrome (LQT9; 611818), Vatta et al. (2006) identified heterozygosity for a 233C-T transition in the CAV3 gene, resulting in a thr78-to-met (T78M) substitution at a highly conserved residue. All 3 patients had a positive family history, but family members declined further genotyping. One patient had biallelic digenic mutations: she was a 14-year-old girl with nonexertional syncope and a 'seizure-like' presentation, who had U waves, sinus bradycardia, and a QTc of 405 ms on ECG, and was found to carry a A913V mutation in the LQT2-associated KCNH2 gene (152427.0024) as well as the T78M mutation. The other 2 patients, who were negative for mutations in other known LQTS genes, were an 8-year-old boy with nonexertional syncope and marked sinus bradycardia with a QTc of 433 ms and an asymptomatic 40-year-old male who had a QTc of 456 ms. The T78M mutation was not found in more than 1,000 control alleles. In frozen necropsy tissue from a 2-month-old black female infant who died of sudden infant death syndrome (SIDS; 272120), Cronk et al. (2007) identified the T78M mutation in the CAV3 gene. Voltage-clamp studies in HEK293 cells demonstrated that the mutant caused a 5-fold increase in late sodium current compared to wildtype. The mutation was not found in 400 reference alleles, of which 200 were ethnically matched. (less)
Likely benign (Feb 19, 2019)	no assertion criteria provided Method: clinical testing	CAV3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004746416.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: 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).
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000280063.1 First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 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. We have classified this variant as likely benign or perhaps conferring low and multifactorial risk (as opposed to causing Mendelian disease). This assessment is based on the presence of the variant in general population samples (reviewed below) and the fact that many of the cases of Mendelian disease with this variant also have a different pathogenic variant in another gene. The CAV3 variant has been reported in 3 unrelated individuals with long QT syndrome, 3 SIDS cases , 1 individual with dilated cardiomyopathy and 1 idiopathic hyper-CK-emia proband (Arnestad et al 2007; Cronk et al 2007; Vatta et al 2006). This is a non-conservative amino acid change with a polar Threonine replaced with a nonpolar Methionine. Threonine is highly conserved at position 78 and studies indicate that this region of the CAV3 gene (codons 74-100) codes for a functionally significant domain of the CAV3 protein (Traverso et al 2008). This domain seems to be involved in caveolae organelle formation in muscle cells however there is no data on function of this region in relation to cardiomyocites. Arnestad et al (2007) identified the variant in 1 out of 182 control individuals. Many of the individuals reported in the literature with this variant also had another variant that was deemed pathogenic. This would suggest that the variant as observed coincidentally. Based on these data, it is unlikely that this CAV3 variant causes Mendelian disease. It remains unknown whether it may contribute to cardiac risk in a more subtle fashion. (less) Number of individuals with the variant: 8
Uncertain significance (-)	no assertion criteria provided Method: research	hypertrophic cardiomyopathy Affected status: yes Allele origin: unknown	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics Accession: SCV005374579.1 First in ClinVar: Oct 20, 2024 Last updated: Oct 20, 2024
not provided (Apr 15, 2012)	no classification provided Method: curation	not specified Affected status: not provided Allele origin: germline	Leiden Muscular Dystrophy (CAV3) Accession: SCV000045700.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013
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Comment:

p.Thr78Met in exon 2 of CAV3: This variant has been reported in 1 individual wit h idiopathic hyper-CK-emia, 3 individuals with LQTS (one of whom had a second pa thogenic variant), 1 individual with DCM and limb-girdle muscular dystrophy (hom ozygous for this variant), and 1 infant with SIDS, and was not detected in >1500 control chromosomes (Reijneveld 2006, Vatta 2006, Cronk 2007, Traverso 2008). H owever, this variant is not expected to have clinical significance because it ha s been identified in 0.4% (276/66492) of European chromosomes and 0.46% (48/1037 6) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org/, dbSNP rs72546668).

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant is associated with the following publications: (PMID: 17275750, 24123366, 23640888, 18253147, 24070816, 24021552, 23465283, 22378279, 22245016, 22595201, 17060380, 26656175, 26159999, 27312022, 29367541, 28648120, 28898996, 30986657, 28988457, 31019283, 31043699)

Comment:

Variant Summary: CAV3 c.233C>T (p.T78M) affects a conserved nucleotide and 4/5 in-silico tools predict this variant to be damaging. The variant is located within the central hydrophobic transmembrane domain (amino acids 75106) of caveolin-3 and has previously been reported to be disease causing. In vitro functional studies have shown that T78M interacts with the cardiac sodium channel to promote increased persistent current. However, it may be meaningless to assess the effects that CAV3 mutations have on a single ion channel without being able to assess the effect on the action potential as a whole due to the complex regulatory nature of the different cardiac ion channels that localize within caveolae. Therefore, the finding that T78M CAV3 expressed heterologously in HEK293 cell lines stably expressing the most common (Q1077del) variant of SCN5A-encoded cardiac sodium channel can cause a five-fold increase in late sodium current should not be considered strong evidence for pathogenicity. Detection of CAV3 T78M in unrelated patients with various diseases has led to its repeated labeling as pathogenic in the literature. However, many of these patients had a co-occurrence that could explain most, if not all, of the presenting phenotype. Additionally, T78M was found in 379/124242 control chromosomes at a frequency of 0.0030505, which is more than 121 times the maximal expected frequency of a CAV3 pathogenic allele (0.000025), suggesting this variant is a benign polymorphism. Patient observations and limited in vitro characterization are not sufficient to conclude that CAV T78M is pathogenic. It is possible that CAV3 T78M may exert a pathogenic effect in association with other genetic factors, however in isolation, the evidence strongly supports a benign classification of this variant. Additionally, several reputable labs classify the variant as benign/likely benign. Taken together, this variant was classified as benign.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.

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. We have classified this variant as likely benign or perhaps conferring low and multifactorial risk (as opposed to causing Mendelian disease). This assessment is based on the presence of the variant in general population samples (reviewed below) and the fact that many of the cases of Mendelian disease with this variant also have a different pathogenic variant in another gene. The CAV3 variant has been reported in 3 unrelated individuals with long QT syndrome, 3 SIDS cases , 1 individual with dilated cardiomyopathy and 1 idiopathic hyper-CK-emia proband (Arnestad et al 2007; Cronk et al 2007; Vatta et al 2006). This is a non-conservative amino acid change with a polar Threonine replaced with a nonpolar Methionine. Threonine is highly conserved at position 78 and studies indicate that this region of the CAV3 gene (codons 74-100) codes for a functionally significant domain of the CAV3 protein (Traverso et al 2008). This domain seems to be involved in caveolae organelle formation in muscle cells however there is no data on function of this region in relation to cardiomyocites. Arnestad et al (2007) identified the variant in 1 out of 182 control individuals. Many of the individuals reported in the literature with this variant also had another variant that was deemed pathogenic. This would suggest that the variant as observed coincidentally. Based on these data, it is unlikely that this CAV3 variant causes Mendelian disease. It remains unknown whether it may contribute to cardiac risk in a more subtle fashion.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
unknown functional consequence			Leiden Muscular Dystrophy (CAV3) Accession: SCV000045700.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts.	Paludan-Müller C	European journal of human genetics : EJHG	2019	PMID: 31043699
A novel elastin gene frameshift mutation in a Russian family with cutis laxa: a case report.	Okuneva EG	BMC dermatology	2019	PMID: 30704477
Amino acid-level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise.	Landstrom AP	Heart rhythm	2018	PMID: 29501670
Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes.	Andreasen L	European journal of human genetics : EJHG	2018	PMID: 29396561
Deleterious protein-altering mutations in the SCN10A voltage-gated sodium channel gene are associated with prolonged QT.	Abou Ziki MD	Clinical genetics	2018	PMID: 28407228
The expression of the rare caveolin-3 variant T78M alters cardiac ion channels function and membrane excitability.	Campostrini G	Cardiovascular research	2017	PMID: 28898996
Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy.	Cecconi M	International journal of molecular medicine	2016	PMID: 27600940
A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort.	Rubattu S	International journal of molecular sciences	2016	PMID: 27483260
CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: Expanding the phenotypic spectrum of caveolinopathies.	Scalco RS	Neuromuscular disorders : NMD	2016	PMID: 27312022
Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval.	Ghouse J	European heart journal	2015	PMID: 26159999
The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome.	Winkel BG	Heart rhythm	2015	PMID: 25757662
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.	Pugh TJ	Genetics in medicine : official journal of the American College of Medical Genetics	2014	PMID: 24503780
Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar.	Rodriguez-Flores JL	Human mutation	2014	PMID: 24123366
'Double trouble': diagnostic challenges in Duchenne muscular dystrophy in patients with an additional hereditary skeletal dysplasia.	Donkervoort S	Neuromuscular disorders : NMD	2013	PMID: 24070816
The role of CAV3 in long-QT syndrome: clinical and functional assessment of a caveolin-3/Kv11.1 double heterozygote versus caveolin-3 single heterozygote.	Hedley PL	Circulation. Cardiovascular genetics	2013	PMID: 24021552
The interaction of caveolin 3 protein with the potassium inward rectifier channel Kir2.1: physiology and pathology related to long qt syndrome 9 (LQT9).	Vaidyanathan R	The Journal of biological chemistry	2013	PMID: 23640888
Mutations in genes encoding cardiac ion channels previously associated with sudden infant death syndrome (SIDS) are present with high frequency in new exome data.	Andreasen C	The Canadian journal of cardiology	2013	PMID: 23465283
Novel rare variants in congenital cardiac arrhythmia genes are frequent in drug-induced torsades de pointes.	Ramirez AH	The pharmacogenomics journal	2013	PMID: 22584458
CAV3 T78M mutation as polymorphic variant in South Italy.	Spadafora P	Neuromuscular disorders : NMD	2012	PMID: 22595201
High prevalence of genetic variants previously associated with LQT syndrome in new exome data.	Refsgaard L	European journal of human genetics : EJHG	2012	PMID: 22378279
Rippling muscle disease and facioscapulohumeral dystrophy-like phenotype in a patient carrying a heterozygous CAV3 T78M mutation and a D4Z4 partial deletion: Further evidence for "double trouble" overlapping syndromes.	Ricci G	Neuromuscular disorders : NMD	2012	PMID: 22245016
Rippling muscle disease and cardiomyopathy associated with a mutation in the CAV3 gene.	Catteruccia M	Neuromuscular disorders : NMD	2009	PMID: 19773168
Caveolin-3 T78M and T78K missense mutations lead to different phenotypes in vivo and in vitro.	Traverso M	Laboratory investigation; a journal of technical methods and pathology	2008	PMID: 18253147
Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3.	Cronk LB	Heart rhythm	2007	PMID: 17275750
Prevalence of long-QT syndrome gene variants in sudden infant death syndrome.	Arnestad M	Circulation	2007	PMID: 17210839
Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome.	Vatta M	Circulation	2006	PMID: 17060380
CAV3 gene mutation analysis in patients with idiopathic hyper-CK-emia.	Reijneveld JC	Muscle & nerve	2006	PMID: 16770780
Molecular and muscle pathology in a series of caveolinopathy patients.	Fulizio L	Human mutation	2005	PMID: 15580566
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAV3	-	-	-	-
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Text-mined citations for rs72546668 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_033337.3(CAV3):c.233C>T (p.Thr78Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72546668 ...