3-8733956-G-C

Position:

• chr3-8733956-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000343849.3(CAV3):​c.80G>C​(p.Arg27Pro) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R27Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAV3 ENST00000343849.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 6.40

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 ENST00000343849.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-8733956-G-C is Pathogenic according to our data. Variant chr3-8733956-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31747.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAV3	NM_033337.3	c.80G>C	p.Arg27Pro	missense_variant	1/2	ENST00000343849.3	NP_203123.1
CAV3	NM_001234.5	c.80G>C	p.Arg27Pro	missense_variant	1/3		NP_001225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAV3	ENST00000343849.3	c.80G>C	p.Arg27Pro	missense_variant	1/2	1	NM_033337.3	ENSP00000341940	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2022

This missense change has been observed in individual(s) with clinical features of autosomal dominant CAV3-related conditions and/or rippling muscle disease (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 27 of the CAV3 protein (p.Arg27Pro). ClinVar contains an entry for this variant (Variation ID: 31747). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg27 amino acid residue in CAV3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10746614, 11431690, 11756609, 11805270, 12807393, 12939441, 15318349, 15580566, 18583131, 18930476, 20472890, 21404291). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. -

CAV3-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2023

The CAV3 c.80G>C variant is predicted to result in the amino acid substitution p.Arg27Pro. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant was reported as likely pathogenic by an outside lab and indicated to segregate in a family with CAV3-related disorder (https://www.ncbi.nlm.nih.gov/clinvar/variation/31747). A different amino acid substitution at this position (p.Arg27Gln) has been repeatedly reported in individuals with features of autosomal dominant CAV3-related disorders (Vorgerd et al. 2001. PubMed ID: 11756609; Figarella-Branger et al 2003. PubMed ID: 12939441; p.Arg26Gln in Brauers et al. 2010. PubMed ID: 20472890; Ishiguro et al. 2018. PubMed ID: 30174172). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (CAV3)

Apr 15, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.51	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	0.72	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.95		Loss of stability (P = 0.0538);Loss of stability (P = 0.0538);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.98

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

Other links and lift over

dbSNP: rs116840778; hg19: chr3-8775642;