3-8745644-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM1 PM5 BP4_Strong BS1 BS2

The NM_033337.3(CAV3):c.233C>T(p.Thr78Met) variant causes a missense change. The variant allele was found at a frequency of 0.00249 in 1,614,100 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T78K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5 B:16 O:1
• Conservation: PhyloP100: 3.78

Genes affected

CAV3 (HGNC:1529): (caveolin 3) This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules. Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), hyperCKemia or rippling muscle disease (RMD). Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites. [provided by RefSeq, Jul 2008]

OXTR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_033337.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-8745644-C-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.017467082).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00301 (459/152316) while in subpopulation AFR AF= 0.00337 (140/41574). AF 95% confidence interval is 0.00294. There are 2 homozygotes in gnomad4. There are 216 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 458 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAV3	NM_033337.3	c.233C>T	p.Thr78Met	missense_variant	2/2	ENST00000343849.3
CAV3	NM_001234.5	c.233C>T	p.Thr78Met	missense_variant	2/3
OXTR	XR_007095681.1	n.1885-3042G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV3	ENST00000343849.3	c.233C>T	p.Thr78Met	missense_variant	2/2	1	NM_033337.3	P1
CAV3	ENST00000397368.2	c.233C>T	p.Thr78Met	missense_variant	2/3	1		P1
CAV3	ENST00000472766.1	n.155+11654C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 458 AN: 152198 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00263 AC: 660 AN: 250926 Hom.: 2 AF XY: 0.00262 AC XY: 355 AN XY: 135622

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000491

Gnomad FIN exome AF: 0.00292

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00243 AC: 3559 AN: 1461784 Hom.: 6 Cov.: 32 AF XY: 0.00243 AC XY: 1764 AN XY: 727178

Gnomad4 AFR exome AF: 0.00355

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00303

Gnomad4 NFE exome AF: 0.00257

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00301 AC: 459 AN: 152316 Hom.: 2 Cov.: 32 AF XY: 0.00290 AC XY: 216 AN XY: 74484

Gnomad4 AFR AF: 0.00337

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.00329

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00353 Hom.: 4

Bravo AF: 0.00293

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00303 AC: 368

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00433

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5 Benign:16 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Aug 16, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 12, 2015	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 17, 2015	- -

not provided Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 12, 2019	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (CAV3)	Apr 15, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2020	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) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CAV3: BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 02, 2019	- -

Long QT syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PP2, PP3, BS1 -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Long QT syndrome 9 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2007	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Mar 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 05, 2018	- -

Long QT syndrome 2/9, digenic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Caveolinopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Long QT syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

CAV3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

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). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.017	T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.83	N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.076	T;T
Sift4G	Uncertain	0.055	T;T
Polyphen		0.97	D;D
Vest4		0.27
MVP		0.99
MPC		1.0
ClinPred		0.063	T
GERP RS		4.6
Varity_R		0.52
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72546668; hg19: chr3-8787330; COSMIC: COSV57479098; COSMIC: COSV57479098;