NM_001267550.2(TTN):c.42154del (p.Ile14052fs) AND Cardiovascular phenotype

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 9, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002389784.1

Allele description

NM_001267550.2(TTN):c.42154del (p.Ile14052fs)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.42154del (p.Ile14052fs)

HGVS:

NC_000002.12:g.178634629del
NG_011618.3:g.201176del
NM_001256850.1:c.37231del
NM_001267550.2:c.42154delMANE SELECT
NM_003319.4:c.14959del
NM_133378.4:c.34450del
NM_133432.3:c.15334del
NM_133437.4:c.15535del
NP_001243779.1:p.Ile12411fs
NP_001254479.1:p.Ile14052Serfs
NP_001254479.2:p.Ile14052fs
NP_003310.4:p.Ile4987fs
NP_596869.4:p.Ile11484fs
NP_597676.3:p.Ile5112fs
NP_597681.4:p.Ile5179fs
LRG_391t1:c.42152del
LRG_391:g.201176del
LRG_391p1:p.Ile14052Serfs
NC_000002.11:g.179499356del
NM_001267550.1:c.42152delA
NM_003319.4:c.14959delA

Protein change:

I11484fs

Molecular consequence:

NM_001256850.1:c.37231del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001267550.2:c.42154del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003319.4:c.14959del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133378.4:c.34450del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133432.3:c.15334del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133437.4:c.15535del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002702004	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Likely pathogenic (Jan 9, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002702004

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Likely pathogenic
(Jan 9, 2020)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Details of each submission

From Ambry Genetics, SCV002702004.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

The c.14959delA variant, located in coding exon 57 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 14959, causing a translational frameshift with a predicted alternate stop codon (p.I4987Sfs*9). This exon is located in the I-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). As such, this alteration is classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Nov 29, 2022

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