rs1553614446

chr3-8745747-C-CGAGATCCAG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP3

The NM_033337.3(CAV3):c.337_345dup(p.Glu113_Gln115dup) variant causes a inframe insertion 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I112I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAV3 NM_033337.3 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Caveolin-3 (size 150) in uniprot entity CAV3_HUMAN there are 80 pathogenic changes around while only 18 benign (82%) 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAV3	NM_033337.3	c.337_345dup	p.Glu113_Gln115dup	inframe_insertion	2/2	ENST00000343849.3
CAV3	NM_001234.5	c.337_345dup	p.Glu113_Gln115dup	inframe_insertion	2/3
OXTR	XR_007095681.1	n.1885-3146_1885-3145insCTGGATCTC		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAV3	ENST00000343849.3	c.337_345dup	p.Glu113_Gln115dup	inframe_insertion	2/2	1	NM_033337.3	P1
CAV3	ENST00000397368.2	c.337_345dup	p.Glu113_Gln115dup	inframe_insertion	2/3	1		P1
CAV3	ENST00000472766.1	n.155+11758_155+11766dup		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2017

In summary, this variant has uncertain impact on CAV3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acid is currently unknown. This variant has not been reported in the literature in individuals with a CAV3-related disease. This variant is not present in population databases (ExAC no frequency). This variant, c.337_345dupGAGATCCAG, results in the insertion of 3 amino acid(s) to the CAV3 protein (p.Glu113_Gln115dup), but otherwise preserves the integrity of the reading frame. -

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: rs1553614446; hg19: chr3-8787433;