rs28936686

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The ENST00000343849.3(CAV3):c.277G>A(p.Ala93Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. A93S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CAV3
ENST00000343849.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1O:1

Conservation

PhyloP100: 9.52

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]

CAV3 links:

OXTR (HGNC:):

OXTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in ENST00000343849.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 3-8745688-G-A is Pathogenic according to our data. Variant chr3-8745688-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8285.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Pathogenic=3, Uncertain_significance=1, not_provided=1}. Variant chr3-8745688-G-A is described in Lovd as [Pathogenic]. Variant chr3-8745688-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-8745688-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CAV3	NM_033337.3 linkuse as main transcript	c.277G>A	p.Ala93Thr	missense_variant	2/2	ENST00000343849.3	NP_203123.1
CAV3	NM_001234.5 linkuse as main transcript	c.277G>A	p.Ala93Thr	missense_variant	2/3		NP_001225.1
OXTR	XR_007095681.1 linkuse as main transcript	n.1885-3086C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CAV3	ENST00000343849.3 linkuse as main transcript	c.277G>A	p.Ala93Thr	missense_variant	2/2	1	NM_033337.3	ENSP00000341940	P1
CAV3	ENST00000397368.2 linkuse as main transcript	c.277G>A	p.Ala93Thr	missense_variant	2/3	1		ENSP00000380525	P1
CAV3	ENST00000472766.1 linkuse as main transcript	n.155+11698G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251184

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000109

AC:

160

AN:

1461812

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000588

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	CAV3: PM1, PS3:Moderate, PP3, PS4:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 14, 2022	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (CAV3)	Apr 15, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2024	Observed in both the homozygous and heterozygous state in a German family with clinical features of rippling muscle disease. Additionally, reported in the homozygous state in a family member reported to have no muscle weakness, although a physical evaluation was not performed on this individual (PMID: 19697367); Identified in a patient with congenital Long QT syndrome (LQTS) in published literature (PMID: 33614747); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Immunohistochemistry and electron microscopy demonstrate loss of caveolin-3 protein and almost complete absence of caveolae in skeletal muscle in an individual homozygous for the p.(A93T) variant (PMID: 12666119); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(A92T); This variant is associated with the following publications: (PMID: 25008241, 15580566, 15668980, 27184587, 19697367, 32419263, 30847666, 25351510, 25630502, 33614747, 32548831, 32528171, Lee2023[article], Leung2023[article], 36556183, 12666119) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 12, 2017	- -

Rippling muscle disease 2

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 31, 2022	Variant summary: CAV3 c.277G>A (p.Ala93Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251184 control chromosomes. This frequency does not allow conclusions about variant significance. c.277G>A has been reported in the literature as a homozygous genotype in families with features of recessive Rippling Muscle Disease and variable phenotypic outcomes ranging from unaffected to mildly affected among obligate carriers (example, Kubisch_2003, Kubisch_2005, Magri_2015, Jacobi_2010). It has also been reported in at-least two individuals (exact zygosity/genotype not specified) in a setting of targeted exome sequencing in a cohort affected by unexplained limb-girdle weakness (example, Topf_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/Likely pathogenic, n=4; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2018	The p.Ala93Thr variant in CAV3 has been reported in the homozygous state in 3 in dividuals with clinical features of rippling muscle disease and segregated with disease in 1 affected family member (Kubisch 2003, Kubisch 2005, Jacobi 2010). I n one family, both heterozygous parents as well as a heterozygous sibling were m ildly affected. Another homozygous sibling reported no features but this was no t confirmed clinically (Jacobi 2010). This variant has been identified in 0.02% (25/126586) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28936686). Studies in patient muscle c ells show a reduction or absence of the CAV3 protein (Kubisch 2003, Kubisch 2005 ). This variant has also been reported in ClinVar (8285). In summary, although a dditional studies are required to fully establish its clinical significance, the p.Ala93Thr variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_Moderat e, PP1_Moderate, PP3, PS4_Supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 21, 2021	- -

Rippling muscle disease 2, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 93 of the CAV3 protein (p.Ala93Thr). This variant is present in population databases (rs28936686, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy and autosomal recessive rippling muscle disease (PMID: 12666119, 15668980, 19697367, 27184587). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8285). 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. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

The p.A93T variant (also known as c.277G>A), located in coding exon 2 of the CAV3 gene, results from a G to A substitution at nucleotide position 277. The alanine at codon 93 is replaced by threonine, an amino acid with similar properties. This alteration (also known as p.A92T) has been reported in the homozygous state in individuals with rippling muscle disease (RMD) and limb-girdle muscular dystrophy, and one study indicated reduction of CAV3 protein expression and caveolae in skeletal muscle from a homozygous individual (Kubisch C et al. Ann. Neurol., 2003 Apr;53:512-20; Kubisch C et al. Ann. Neurol., 2005 Feb;57:303-4; Magri F et al. Muscle Nerve, 2016 May). In one family, heterozygous individuals did not exhibit any symptoms of RMD, while another family demonstrated mild symptoms of muscle weakness in heterozygous family members (Kubisch C et al. Ann. Neurol., 2005 Feb;57:303-4; Jacobi C et al. Muscle Nerve, 2010 Jan;41:128-32). This variant was also described in a late onset vacuolar myopathy cohort, as seen in a heterozygous proband with elevated serum CK levels and in his heterozygous mother with polyneuropathy; no cardiac findings were reported (Mair D et al. Brain Pathol., 2020 Sep;30:877-896). This variant has also been reported in hypertrophic cardiomyopathy and dilated cardiomyopathy genetic testing cohorts; however, clinical details were limited and additional variants were detected in some cases (Lopes LR et al. Heart, 2015 Feb;101:294-301; van Lint FHM et al, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by BayesDel analysis. Based on the supporting evidence, this variant is likely to be pathogenic for autosomal recessive caveolinopathy; however, the clinical significance for autosomal dominant caveolinopathy is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.92

Gain of glycosylation at A93 (P = 0.0826);Gain of glycosylation at A93 (P = 0.0826);

MVP

0.98

MPC

1.4

ClinPred

0.69

GERP RS

4.8

Varity_R

0.95

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over