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NM_001267550.2(TTN):c.107889del (p.Lys35963fs) AND TTN-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 12, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV004532474.3

Allele description [Variation Report for NM_001267550.2(TTN):c.107889del (p.Lys35963fs)]

NM_001267550.2(TTN):c.107889del (p.Lys35963fs)

Genes:
TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.107889del (p.Lys35963fs)
HGVS:
  • NC_000002.12:g.178527101del
  • NG_011618.3:g.308704del
  • NG_051363.1:g.9275del
  • NM_001256850.1:c.102966del
  • NM_001267550.2:c.107889delMANE SELECT
  • NM_003319.4:c.80694del
  • NM_133378.4:c.100185del
  • NM_133432.3:c.81069del
  • NM_133437.4:c.81270del
  • NP_001243779.1:p.Lys34322fs
  • NP_001254479.2:p.Lys35963fs
  • NP_003310.4:p.Lys26898fs
  • NP_596869.4:p.Lys33395fs
  • NP_597676.3:p.Lys27023fs
  • NP_597681.4:p.Lys27090fs
  • LRG_391t1:c.107889del
  • LRG_391:g.308704del
  • NC_000002.11:g.179391826del
  • NC_000002.11:g.179391828del
  • NM_001256850.1:c.102966delA
  • NM_001267550.1:c.107889del
  • NM_001267550.2:c.107889delAMANE SELECT
  • NM_003319.4:c.80694delA
  • NM_133378.4:c.100185del
  • NM_133378.4:c.100185delA
  • p.K34322NfsX9
  • p.Lys35963AsnfsTer9
Nucleotide change:
AJ277892.2:g.293378delA
Protein change:
K26898fs
Links:
dbSNP: rs281864930
NCBI 1000 Genomes Browser:
rs281864930
Molecular consequence:
  • NM_001256850.1:c.102966del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001267550.2:c.107889del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_003319.4:c.80694del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133378.4:c.100185del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133432.3:c.81069del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133437.4:c.81270del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
TTN-related disorder
Synonyms:
TTN-related condition; TTN-Related Disorders; TTN-related disease
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004719340PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Jan 12, 2024) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004719340.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The TTN c.107889delA variant is predicted to result in a frameshift and premature protein termination (p.Lys35963Asnfs*9). This variant has been reported in individuals with tibial muscular dystrophy, centronuclear myopathy, dilated cardiomyopathy and sudden cardiac death (Hackman et al. 2008. PubMed ID: 18948003; Ceyhan-Birsoy et al. 2013. PubMed ID: 23975875; Evilä et al. 2014. PubMed ID: 24395473; Evilä et al. 2015. PubMed ID: 26627873; Campuzano et al. 2015. PubMed ID: 26516846). The c.107889delA variant is located in the M-band region of the TTN protein and other premature stop variants in this exon have previously been reported to be pathogenic for recessive and dominant TTN-related disorders (Human Gene Mutation Database). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%); however, this analysis in muscle tissue was not performed (Roberts A.M. et al. 2015. PMID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating this variant is more likely to be disease causing (Roberts A.M. et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). Many cases of recessive TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy O. et al. 2013. PMID: 23975875; Chauveau C et al. 2014. PMID: 24105469; Evilä A et al. 2016. PMID: 27796757; Ge et al. 2019. PubMed ID: 31053406). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, the c.107889delA variant is categorized as pathogenic for TTN-related disorders.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024