rs587777135

Variant names:

• chr10-65966713-CCAA-C
• rs587777135
• NM_013266.4:c.2296_2298delTTG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_013266.4(CTNNA3):​c.2296_2298delTTG​(p.Leu766del) variant causes a conservative 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: CTNNA3 NM_013266.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 7.51
• Publications: 1 publications found

Genes affected

CTNNA3 (HGNC:2511): (catenin alpha 3) This gene encodes a protein that belongs to the vinculin/alpha-catenin family. The encoded protein plays a role in cell-cell adhesion in muscle cells. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia, familial 13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

CTNNA3 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 13

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_013266.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 10-65966713-CCAA-C is Pathogenic according to our data. Variant chr10-65966713-CCAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 100657.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNA3	NM_013266.4	c.2296_2298delTTG	p.Leu766del	conservative_inframe_deletion	Exon 17 of 18	ENST00000433211.7	NP_037398.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNA3	ENST00000433211.7	c.2296_2298delTTG	p.Leu766del	conservative_inframe_deletion	Exon 17 of 18	1	NM_013266.4	ENSP00000389714.1

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:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 13 Pathogenic:1 Other:1

Jan 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Apr 18, 2017

Rampazzo Lab, Human Molecular Genetics Unit, University of Padua

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This variant was not found in 250 ethnically matched healthy controls (500 chromosomes), in dbSNP, in 1000 Genomes Project database, in Exome Variant Server or in Exome Aggregation Consortium. The variation causes the deletion of leucine in position 765 and the affected residue is strongly conserved among species. Yeast two-hybrid and cell transfection studies showed that the p.del765L mutant protein had a much stronger dimerization potential and formed aggresomes in HEK293T cells. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=69/31	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777135; hg19: chr10-67726471;