rs116840789

Positions:

Variant summary

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

The NM_033337.3(CAV3):c.136G>A(p.Ala46Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A46S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CAV3
NM_033337.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O: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 Pathogenic. Variant got 18 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-8745547-G-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 3-8745547-G-A is Pathogenic according to our data. Variant chr3-8745547-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-8745547-G-A is described in Lovd as [Pathogenic]. Variant chr3-8745547-G-A is described in Lovd as [Pathogenic]. Variant chr3-8745547-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CAV3	NM_033337.3 linkuse as main transcript	c.136G>A	p.Ala46Thr	missense_variant	2/2	ENST00000343849.3	NP_203123.1
CAV3	NM_001234.5 linkuse as main transcript	c.136G>A	p.Ala46Thr	missense_variant	2/3		NP_001225.1
OXTR	XR_007095681.1 linkuse as main transcript	n.1885-2945C>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.136G>A	p.Ala46Thr	missense_variant	2/2	1	NM_033337.3	ENSP00000341940	P1
CAV3	ENST00000397368.2 linkuse as main transcript	c.136G>A	p.Ala46Thr	missense_variant	2/3	1		ENSP00000380525	P1
CAV3	ENST00000472766.1 linkuse as main transcript	n.155+11557G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727184

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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

Cov.:

Alfa

AF:

0.0000454

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (CAV3)	Apr 15, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2022	Published functional studies demonstrate a damaging effect (Brauers et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15580566, 20229577, 11431690, 31862442, 20472890, 22976939, 21660982, 18583131, 11001938, 26947586, 28807458, 33963534, 32528171, 25630502, 17994539) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 07, 2016	- -

Elevated circulating creatine kinase concentration

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 46 of the CAV3 protein (p.Ala46Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with caveolinopathies (PMID: 11001938, 11431690, 15580566, 18583131, 20229577, 21660982, 22976939, 26947586). 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. This variant is also known as p.Ala45Thr. ClinVar contains an entry for this variant (Variation ID: 8281). 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: 11431690, 20472890). For these reasons, this variant has been classified as Pathogenic. -

Rippling muscle disease 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2021

The p.A46T pathogenic mutation (also known as p.A45T and c.136G>A), located in coding exon 2 of the CAV3 gene, results from a G to A substitution at nucleotide position 136. The alanine at codon 46 is replaced by threonine, an amino acid with similar properties. This mutation has been reported in individuals with a range of caveolinopathies, including limb girdle muscular dystrophy type 1C, rippling muscle disease, hyperCKemia, and asymmetric distal myopathy (Fulizio L et al. Hum Mutat, 2005 Jan;25:82-9; Guglieri M et al. Hum Mutat, 2008 Feb;29:258-66; Aboumousa A et al. Neuromuscul Disord, 2008 Jul;18:572-8; Harris E et al. Orphanet J Rare Dis, 2017 09;12:151). This variant also showed segregation with affected phenotypes across multiple generations in a large Swedish family (Sundblom J et al. Muscle Nerve, 2010 Jun;41:751-7). In addition, at least three reportedly de novo cases with absent or reduced CAV3 expression have been documented (Herrmann R et al. Hum Mol Genet, 2000 Sep;9:2335-40; Arias Gómez M et al. Muscle Nerve, 2011 Jul;44:126-8; Chen J et al. Neuropathology, 2016 Oct;36:485-489). Limited functional studies also demonstrated lower CAV3 surface expression (Brauers E et al. Am J Pathol, 2010 Jul;177:261-70). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Myopathy with tubular aggregates

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PM1+PM2+PM6+PP2+PP3+PP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.93

Gain of glycosylation at A46 (P = 0.043);Gain of glycosylation at A46 (P = 0.043);

MVP

1.0

MPC

1.4

ClinPred

1.0

GERP RS

4.8

Varity_R

0.94

gMVP

0.92

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