rs778914298

chr3-8733882-GGCAGAAGA-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_033337.3(CAV3):c.10_17del(p.Glu4HisfsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000499 in 1,601,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CAV3 NM_033337.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 5.98

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 93 pathogenic variants in the truncated region.
• PP5: Variant 3-8733882-GGCAGAAGA-G is Pathogenic according to our data. Variant chr3-8733882-GGCAGAAGA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290919.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=2}. Variant chr3-8733882-GGCAGAAGA-G is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd at 5 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAV3	NM_033337.3	c.10_17del	p.Glu4HisfsTer17	frameshift_variant	1/2	ENST00000343849.3
CAV3	NM_001234.5	c.10_17del	p.Glu4HisfsTer17	frameshift_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV3	ENST00000343849.3	c.10_17del	p.Glu4HisfsTer17	frameshift_variant	1/2	1	NM_033337.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

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: 0.00000207 AC: 3 AN: 1449754 Hom.: 0 AF XY: 0.00000277 AC XY: 2 AN XY: 721950

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.00

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: 0.0000167

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152136 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74326

Gnomad4 AFR AF: 0.000121

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 20, 2022	- -

Elevated circulating creatine kinase concentration Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 11, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 290919). This variant has not been reported in the literature in individuals affected with CAV3-related conditions. This variant is present in population databases (rs778914298, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Glu4Hisfs*17) in the CAV3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAV3 are known to be pathogenic (PMID: 18487559). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2021

The c.10_17delGAAGAGCA variant, located in coding exon 1 of the CAV3 gene, results from a deletion of 8 nucleotides at nucleotide positions 10 to 17, causing a translational frameshift with a predicted alternate stop codon (p.E4Hfs*17). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although truncating variants have been implicated in autosomal recessive caveolinopathy, loss of function has not been established as a mechanism of disease for autosomal dominant caveolinopathy (Müller JS et al. Neuromuscul Disord, 2006 Jul;16:432-6; Ueyama H et al. Neuromuscul Disord, 2007 Jul;17:558-61; Traverso M et al. J Neurol Neurosurg Psychiatry, 2008 Jun;79:735-7). Based on the supporting evidence, this variant is expected to be pathogenic for autosomal recessive caveolinopathy when present along with a second pathogenic variant on the other allele; however, the clinical significance of this variant in the heterozygous state is unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs778914298; hg19: chr3-8775568;