NM_001267550.2(TTN):c.44831del (p.Phe14944fs) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 26, 2023
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:: RCV003360567.2

Allele description [Variation Report for NM_001267550.2(TTN):c.44831del (p.Phe14944fs)]

NM_001267550.2(TTN):c.44831del (p.Phe14944fs)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.44831del (p.Phe14944fs)

HGVS:

NC_000002.12:g.178622753del
NG_011618.3:g.213051del
NM_001256850.1:c.39908del
NM_001267550.2:c.44831delMANE SELECT
NM_003319.4:c.17636del
NM_133378.4:c.37127del
NM_133432.3:c.18011del
NM_133437.4:c.18212del
NP_001243779.1:p.Phe13303fs
NP_001254479.1:p.Phe14944Serfs
NP_001254479.2:p.Phe14944fs
NP_003310.4:p.Phe5879fs
NP_596869.4:p.Phe12376fs
NP_597676.3:p.Phe6004fs
NP_597681.4:p.Phe6071fs
LRG_391t1:c.44830del
LRG_391:g.213051del
LRG_391p1:p.Phe14944Serfs
NC_000002.11:g.179487480del
NM_001267550.1:c.44830delT
NM_003319.4:c.17636delT

Protein change:

F12376fs

Molecular consequence:

NM_001256850.1:c.39908del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001267550.2:c.44831del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003319.4:c.17636del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133378.4:c.37127del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133432.3:c.18011del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133437.4:c.18212del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV004053209	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jun 26, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004053209

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jun 26, 2023)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Ambry Genetics, SCV004053209.2

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

Description

The c.17636delT variant, located in coding exon 70 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 17636, causing a translational frameshift with a predicted alternate stop codon (p.F5879Sfs*2). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: May 1, 2024

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