rs121909278

chr3-8733956-G-Achr3-8733956-G-Cchr3-8733956-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_033337.3(CAV3):c.80G>A(p.Arg27Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,612,028 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R27P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAV3 NM_033337.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 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 18 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 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 chr3-8733955-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 31722.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 3-8733956-G-A is Pathogenic according to our data. 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. Variant chr3-8733956-G-A is described in Lovd as [Pathogenic]. Variant chr3-8733956-G-A is described in Lovd as [Pathogenic]. Variant chr3-8733956-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.80G>A	p.Arg27Gln	missense_variant	1/2	ENST00000343849.3
CAV3	NM_001234.5	c.80G>A	p.Arg27Gln	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV3	ENST00000343849.3	c.80G>A	p.Arg27Gln	missense_variant	1/2	1	NM_033337.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152030 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459998 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726420

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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 AF: 0.00000658 AC: 1 AN: 152030 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74248

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 02, 2020	PS3, PS4, PM2, PP1, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 22, 2018	Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Very strong co-segregation with disease. However, available data lack unaffected family members. One de novo case with parental identity confirmed. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2018	The R27Q pathogenic variant in the CAV3 gene has been reported previously in multiple individuals in a family with autosomal dominant rippling muscle disease (RMD), limb-girdle muscular dystrophy type 1C (LGMD1C), or a combination of both conditions (Fee et al., 2004). The R27Q pathogenic variant has also been reported as a de novo variant in two unrelated individuals with hyperCKemia (Carbone et al., 2000; CAV3 LOVD). Functional studies have shown that R27Q decreases nerve and epidermal growth factor signaling (Brauers et al., 2010). In those studies, R27Q was reported as R26Q due to the use of alternative nomenclature. The R27Q pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R27Q pathogenic variant alters a conserved position predicted to be within the N-terminal cytoplasmic domain, and several pathogenic variants (R27G, D28E, P29T, and P29L) have been reported in nearby residues, in association with caveolinopathies (Stenson et al., 2014). Therefore, we interpret R27Q as a pathogenic variant, and its presence is consistent with a diagnosis of a CAV3-related disorder -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -

Rippling muscle disease 2 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 15, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Pathogenic, for Caveolinopathies (creatine phosphokinase, elevated serum. HyperCKemia. Rippling muscle disease 2 (RMD2). Myopathy, distal, Tateyama type (MPDT). Limb-girdle muscular dystrophy 1C (LGMD1C)), in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:10746614). PS2 => De novo (paternity and maternity confirmed) (PMID:11756609). PS3 => Well-established functional studies show a deleterious effect (PMID:12939441) (PMID:15580566). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate. -

Distal myopathy, Tateyama type Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 13, 2020	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (CAV3)	Apr 15, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 15, 2009	- -

Elevated circulating creatine kinase concentration;C1832560:Rippling muscle disease 2;C2678485:Long QT syndrome 9;C3280443:Distal myopathy, Tateyama type;C3495498:Hypertrophic cardiomyopathy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 26, 2021

- -

Elevated circulating creatine kinase concentration Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2009

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 27 of the CAV3 protein (p.Arg27Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with distal myopathy, hyperCKemia, limb-girdle muscular dystrophy type 1C, and/or rippling muscle disease (PMID: 10746614, 11431690, 11756609, 11805270, 12807393, 12939441, 15318349, 15580566, 18583131, 18930476, 20472890, 21404291). 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. ClinVar contains an entry for this variant (Variation ID: 8283). 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: 12839838, 14633633, 19380584, 20472890). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.46	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	0.64	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.99		Loss of stability (P = 0.1046);Loss of stability (P = 0.1046);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.94

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;