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rs116840778

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_033337.3(CAV3):c.80G>A(p.Arg27Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,612,028 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R27P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CAV3
NM_033337.3 missense

Scores

14
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 6.40
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]
SSUH2 (HGNC:24809): (ssu-2 homolog) Involved in odontogenesis. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_033337.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-8733955-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 31722.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 3-8733956-G-A is Pathogenic according to our data. Variant chr3-8733956-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-8733956-G-A is described in Lovd as [Pathogenic]. Variant chr3-8733956-G-A is described in Lovd as [Pathogenic]. Variant chr3-8733956-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CAV3NM_033337.3 linkuse as main transcriptc.80G>A p.Arg27Gln missense_variant 1/2 ENST00000343849.3
CAV3NM_001234.5 linkuse as main transcriptc.80G>A p.Arg27Gln missense_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CAV3ENST00000343849.3 linkuse as main transcriptc.80G>A p.Arg27Gln missense_variant 1/21 NM_033337.3 P1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152030
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459998
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726420
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152030
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74248
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 09, 2018The R27Q pathogenic variant in the CAV3 gene has been reported previously in multiple individuals in a family with autosomal dominant rippling muscle disease (RMD), limb-girdle muscular dystrophy type 1C (LGMD1C), or a combination of both conditions (Fee et al., 2004). The R27Q pathogenic variant has also been reported as a de novo variant in two unrelated individuals with hyperCKemia (Carbone et al., 2000; CAV3 LOVD). Functional studies have shown that R27Q decreases nerve and epidermal growth factor signaling (Brauers et al., 2010). In those studies, R27Q was reported as R26Q due to the use of alternative nomenclature. The R27Q pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R27Q pathogenic variant alters a conserved position predicted to be within the N-terminal cytoplasmic domain, and several pathogenic variants (R27G, D28E, P29T, and P29L) have been reported in nearby residues, in association with caveolinopathies (Stenson et al., 2014). Therefore, we interpret R27Q as a pathogenic variant, and its presence is consistent with a diagnosis of a CAV3-related disorder -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 24, 2017- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 26, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2019- -
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsJun 22, 2018Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Very strong co-segregation with disease. However, available data lack unaffected family members. One de novo case with parental identity confirmed. -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicNov 02, 2020PS3, PS4, PM2, PP1, PP3, PP4 -
Rippling muscle disease 2 Pathogenic:3
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 15, 2009- -
Pathogenic, criteria provided, single submittercurationSIB Swiss Institute of BioinformaticsMay 31, 2018This variant is interpreted as a Pathogenic, for Caveolinopathies (creatine phosphokinase, elevated serum. HyperCKemia. Rippling muscle disease 2 (RMD2). Myopathy, distal, Tateyama type (MPDT). Limb-girdle muscular dystrophy 1C (LGMD1C)), in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:10746614). PS2 => De novo (paternity and maternity confirmed) (PMID:11756609). PS3 => Well-established functional studies show a deleterious effect (PMID:12939441) (PMID:15580566). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate. -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterAug 26, 2022- -
Distal myopathy, Tateyama type Pathogenic:2Other:1
not provided, no classification providedcurationLeiden Muscular Dystrophy (CAV3)Apr 15, 2012- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 15, 2009- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenMar 13, 2020- -
Elevated circulating creatine kinase concentration;C1832560:Rippling muscle disease 2;C2678485:Long QT syndrome 9;C3280443:Distal myopathy, Tateyama type;C3495498:Hypertrophic cardiomyopathy 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 26, 2021- -
Elevated circulating creatine kinase concentration Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 15, 2009- -
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 18, 2023This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 27 of the CAV3 protein (p.Arg27Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with distal myopathy, hyperCKemia, limb-girdle muscular dystrophy type 1C, and/or rippling muscle disease (PMID: 10746614, 11431690, 11756609, 11805270, 12807393, 12939441, 15318349, 15580566, 18583131, 18930476, 20472890, 21404291). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8283). 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 disruptive. Experimental studies have shown that this missense change affects CAV3 function (PMID: 12839838, 14633633, 19380584, 20472890). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.97
D;D
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H;H
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.7
D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.94
MutPred
0.99
Loss of stability (P = 0.1046);Loss of stability (P = 0.1046);
MVP
1.0
MPC
1.6
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.94
gMVP
0.94

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: rs116840778; hg19: chr3-8775642; API