rs116840796

chr3-8745594-C-Achr3-8745594-C-Gchr3-8745594-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_033337.3(CAV3):c.183C>A(p.Ser61Arg) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S61N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 2.37

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]

OXTR (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 3-8745594-C-A is Pathogenic according to our data. Variant chr3-8745594-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31729.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-8745594-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAV3	NM_033337.3	c.183C>A	p.Ser61Arg	missense_variant	2/2	ENST00000343849.3
CAV3	NM_001234.5	c.183C>A	p.Ser61Arg	missense_variant	2/3
OXTR	XR_007095681.1	n.1885-2992G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV3	ENST00000343849.3	c.183C>A	p.Ser61Arg	missense_variant	2/2	1	NM_033337.3	P1
CAV3	ENST00000397368.2	c.183C>A	p.Ser61Arg	missense_variant	2/3	1		P1
CAV3	ENST00000472766.1	n.155+11604C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

CAV3-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2022

The CAV3 c.183C>A variant is predicted to result in the amino acid substitution p.Ser61Arg. This variant has been reported in the heterozygous state in an individual with myopathy, dystrophic muscle biopsy pathology, and no CAV3 protein detected by western blot (Table 1, Fulizio et al 2005. PubMed ID: 15580566). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A C-to-G change at the same nucleotide position resulting in the the same amino acid change has been reported in a father and son with familial hyperckemia and calf hypertrophy, as well as another individual with myopathy (Otero-Loperena. 2020. PubMed ID: 33002912; Stavusis et al. 2015. PubMed ID: 25630502). This variant is interpreted as likely pathogenic. -

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	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.96		Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.99
gMVP		0.99

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: rs116840796; hg19: chr3-8787280;