rs116840789
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_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. 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. A46E) 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
NM_033337.3 missense
Scores
12
5
1
Clinical Significance
Conservation
PhyloP100: 9.52
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a topological_domain Cytoplasmic (size 82) in uniprot entity CAV3_HUMAN there are 61 pathogenic changes around while only 13 benign (82%) in NM_033337.3
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr3-8745548-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8282.Status of the report is criteria_provided_single_submitter, 1 stars.
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]. 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 | UniProt |
---|---|---|---|---|---|---|---|
CAV3 | NM_033337.3 | c.136G>A | p.Ala46Thr | missense_variant | 2/2 | ENST00000343849.3 | |
CAV3 | NM_001234.5 | c.136G>A | p.Ala46Thr | missense_variant | 2/3 | ||
OXTR | XR_007095681.1 | n.1885-2945C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAV3 | ENST00000343849.3 | c.136G>A | p.Ala46Thr | missense_variant | 2/2 | 1 | NM_033337.3 | P1 | |
CAV3 | ENST00000397368.2 | c.136G>A | p.Ala46Thr | missense_variant | 2/3 | 1 | P1 | ||
CAV3 | ENST00000472766.1 | n.155+11557G>A | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461776Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727184
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
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1461776
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32
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0
AN XY:
727184
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GnomAD4 genome ? Cov.: 32
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32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 07, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 06, 2017 | - - |
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 | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2020 | - - |
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 | Invitae | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of glycosylation at A46 (P = 0.043);Gain of glycosylation at A46 (P = 0.043);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at