chr3-8745655-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_033337.3(CAV3):​c.244G>A​(p.Val82Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CAV3
NM_033337.3 missense

Scores

1
2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 3.43
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a topological_domain Cytoplasmic (size 82) in uniprot entity CAV3_HUMAN there are 46 pathogenic changes around while only 9 benign (84%) in NM_033337.3
BP4
Computational evidence support a benign effect (MetaRNN=0.2919835).
BS2
High AC in GnomAd4 at 11 AD,Digenic gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CAV3NM_033337.3 linkuse as main transcriptc.244G>A p.Val82Ile missense_variant 2/2 ENST00000343849.3 NP_203123.1
CAV3NM_001234.5 linkuse as main transcriptc.244G>A p.Val82Ile missense_variant 2/3 NP_001225.1
OXTRXR_007095681.1 linkuse as main transcriptn.1885-3053C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CAV3ENST00000343849.3 linkuse as main transcriptc.244G>A p.Val82Ile missense_variant 2/21 NM_033337.3 ENSP00000341940 P1
CAV3ENST00000397368.2 linkuse as main transcriptc.244G>A p.Val82Ile missense_variant 2/31 ENSP00000380525 P1
CAV3ENST00000472766.1 linkuse as main transcriptn.155+11665G>A intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000956
AC:
24
AN:
250942
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135662
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.0000994
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000705
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000160
AC:
234
AN:
1461784
Hom.:
0
Cov.:
32
AF XY:
0.000154
AC XY:
112
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.000388
Gnomad4 AMR exome
AF:
0.000291
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000156
Gnomad4 OTH exome
AF:
0.000497
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152286
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000883
Hom.:
0
Bravo
AF:
0.0000869
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000576
AC:
7
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 17, 2023- -
Uncertain significance, no assertion criteria providedprovider interpretationStanford Center for Inherited Cardiovascular Disease, Stanford UniversityDec 16, 2016p.Val82Ile (c.244G>A) in exon 2 of the CAV3 gene (NM_033337.2) We have seen this variant in a person with HCM who also had a very likely pathogenic MYBPC3 variant. Testing was performed by Invitae. Given the lack of gene level evidence associating the CAV3 gene with hypertrophic cardiomyopathy and case data linking the variant to LongQT syndrome that is somewhat undercut by population frequency, we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene level evidence for CAV3 Both knockout and transgenic mouse models of CAV3 show evidence of HCM with progressive diastolic dysfunction (Aravamudan et al, 2003; Ohsawa et al, 2004). Despite this, human data points towards CAV3 variants causing skeletal muscle disease, not cardiomyopathy. Hayashi et al (2004) reported two siblings with HCM and p.T63S in CAV3. The variant was not inherited from their mother, so it was assumed to have come from their affected father, who was unavailable for study. Variant level evidence for CAV3 Val82Ile The Val82Ile variant has been seen in at least 3 unrelated cases of Long QT syndrome (not including this patient's family). It has not been reported in association with cardiomyopathy. Lariccia et al., 2014 reported it in a person with adult-onset sudden cardiac death. Lieve et al., 2013 reported the variant in a person with Long QT who also had a varian in KCNH2. The Invitae report notes that, "The valine residue is moderately conserved and there is a small physicochemical difference between valine and Isoleucine. An abstract from the 35th congresso nazionale Della Soicieta Italiana di Farmacologia reported it in an Italian patient with Long QT (http://congresso.sifweb.org/archivio/cong35/congresso_abs_view.php?id=244). Lariccia et al., 2014 reported that the variant caused increased protein expression, reduced targeting to the plasma membrane and impaired extracellular signal regulated kinase activation. The variant was reported online in 7 of 60,401 individuals (MAF: 0.0058%) in the Exome Aggregation Consortium Dataset (EXAC; http://exac.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino descent. Specifically, the variant was observed in 3 of 33,239 individuals of non-Finnish European descent (0.005% MAF), 1 of 5,189 people of African descent (MAF: 0.0096%), 1 of 5752 people of Latino descent (MAF 0.0087%), 1 of 8,210 people of South Asian descent (MAF: 0.006%, and 1 of 449 people of Other descent (MAF: 0.001%) . The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 24, 2021In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24917393, 23631430, 31737537, 30847666) -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 27, 2018- -
Long QT syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMendelicsJun 24, 2022- -
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioMar 22, 2016- -
See cases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinMay 19, 2020ACMG classification criteria: PS3, PS4, PP2 -
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 82 of the CAV3 protein (p.Val82Ile). This variant is present in population databases (rs112626848, gnomAD 0.03%). This missense change has been observed in individual(s) with various cardiac conditions (PMID: 23631430, 24917393, 30847666, 31737537). ClinVar contains an entry for this variant (Variation ID: 279733). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CAV3 function (PMID: 24917393). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 27, 2022The p.V82I variant (also known as c.244G>A), located in coding exon 2 of the CAV3 gene, results from a G to A substitution at nucleotide position 244. The valine at codon 82 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in association with long QT syndrome and sudden cardiac death (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Lariccia V et al. J. Biomed. Sci., 2014 Jun;21:58). This alteration was also noted to have a cell expression profile that was altered from the wildtype (Lariccia V et al. J. Biomed. Sci., 2014 Jun;21:58). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
21
DANN
Benign
0.64
DEOGEN2
Uncertain
0.51
D;D
Eigen
Benign
-1.1
Eigen_PC
Benign
-0.85
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.70
.;T
M_CAP
Pathogenic
0.59
D
MetaRNN
Benign
0.29
T;T
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
-1.3
N;N
MutationTaster
Benign
0.54
D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
0.080
N;N
REVEL
Benign
0.27
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0080
B;B
Vest4
0.35
MVP
0.47
MPC
0.43
ClinPred
0.025
T
GERP RS
2.8
Varity_R
0.042
gMVP
0.51

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs112626848; hg19: chr3-8787341; COSMIC: COSV57479298; COSMIC: COSV57479298; API