Genetic Variant CAV3:p.Ala46Thr (chr3-8745547-G-A) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_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 Uncertain significance.

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:10O:1

Conservation

PhyloP100: 9.52

Publications

15 publications found

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:8529): (oxytocin receptor) The protein encoded by this gene belongs to the G-protein coupled receptor family and acts as a receptor for oxytocin. Its activity is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. The oxytocin-oxytocin receptor system plays an important role in the uterus during parturition. [provided by RefSeq, Jul 2008]

OXTR links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 82) in uniprot entity CAV3_HUMAN there are 14 pathogenic changes around while only 6 benign (70%) 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 chr3-8745548-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 8282.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.83011 (below the threshold of 3.09). Trascript score misZ: 0.9876 (below the threshold of 3.09). GenCC associations: The gene is linked to rippling muscle disease 2, hypertrophic cardiomyopathy 1, long QT syndrome 9, distal myopathy, Tateyama type, inherited rippling muscle disease, Brugada syndrome, autosomal dominant limb-girdle muscular dystrophy type 1C, caveolinopathy, long QT syndrome.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 8281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033337.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAV3	NM_033337.3	MANE Select	c.136G>A	p.Ala46Thr	missense	Exon 2 of 2	NP_203123.1
	CAV3	NM_001234.5		c.136G>A	p.Ala46Thr	missense	Exon 2 of 3	NP_001225.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CAV3	ENST00000343849.3	TSL:1 MANE Select	c.136G>A	p.Ala46Thr	missense	Exon 2 of 2	ENSP00000341940.2
CAV3	ENST00000397368.2	TSL:1	c.136G>A	p.Ala46Thr	missense	Exon 2 of 3	ENSP00000380525.2
CAV3	ENST00000472766.1	TSL:2	n.155+11557G>A		intron	N/A

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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111932

Other (OTH)

AF:

0.00

AC:

AN:

60396

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000273

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Other:1

Jan 06, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 15, 2012

Leiden Muscular Dystrophy (CAV3)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

Aug 31, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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)

Oct 22, 2024

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 07, 2016

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Elevated circulating creatine kinase concentration

Pathogenic:1

Jan 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Rippling muscle disease 2

Pathogenic:1

Jan 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Long QT syndrome

Pathogenic:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Cardiovascular phenotype

Pathogenic:1

Feb 19, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Mar 01, 2024

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PM1+PM2+PM6+PP2+PP3+PP5

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

PhyloP100

9.5

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.93

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

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over