rs116840800

Positions:

• chr3-8745596-ACACCACCTT-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_033337.3(CAV3):​c.189_197delCACCTTCAC​(p.Thr64_Thr66del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAV3 NM_033337.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.87

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:8529): (oxytocin receptor) The protein encoded by this gene belongs to the G-protein coupled receptor family and acts as a receptor for oxytocin. Its activity is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. The oxytocin-oxytocin receptor system plays an important role in the uterus during parturition. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 82) in uniprot entity CAV3_HUMAN there are 46 pathogenic changes around while only 9 benign (84%) in NM_033337.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_033337.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 3-8745596-ACACCACCTT-A is Pathogenic according to our data. Variant chr3-8745596-ACACCACCTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 8277.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-8745596-ACACCACCTT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAV3	NM_033337.3	c.189_197delCACCTTCAC	p.Thr64_Thr66del	disruptive_inframe_deletion	2/2	ENST00000343849.3	NP_203123.1
CAV3	NM_001234.5	c.189_197delCACCTTCAC	p.Thr64_Thr66del	disruptive_inframe_deletion	2/3		NP_001225.1
OXTR	XR_007095681.1	n.1885-3003_1885-2995delAAGGTGGTG		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAV3	ENST00000343849.3	c.189_197delCACCTTCAC	p.Thr64_Thr66del	disruptive_inframe_deletion	2/2	1	NM_033337.3	ENSP00000341940.2
CAV3	ENST00000397368.2	c.189_197delCACCTTCAC	p.Thr64_Thr66del	disruptive_inframe_deletion	2/3	1		ENSP00000380525.2
CAV3	ENST00000472766.1	n.155+11610_155+11618delCACCTTCAC		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Rippling muscle disease 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 03, 1999

- -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (CAV3)

Apr 15, 2012

- -

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: rs199476331; hg19: chr3-8787282;