NM_001267550.2(TTN):c.12405del (p.Asn4135fs) AND Cardiovascular phenotype

Clinical significance:Likely pathogenic (Last evaluated: Feb 2, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000618476.1

Allele description [Variation Report for NM_001267550.2(TTN):c.12405del (p.Asn4135fs)]

NM_001267550.2(TTN):c.12405del (p.Asn4135fs)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.12405del (p.Asn4135fs)
HGVS:
  • NC_000002.12:g.178740828del
  • NG_011618.3:g.94975del
  • NM_001256850.1:c.11454del
  • NM_001267550.2:c.12405delMANE SELECT
  • NM_003319.4:c.11316del
  • NM_133378.4:c.10361-2468del
  • NM_133432.3:c.11691del
  • NM_133437.4:c.11892del
  • NP_001243779.1:p.Asn3818fs
  • NP_001254479.2:p.Asn4135fs
  • NP_003310.4:p.Asn3772fs
  • NP_597676.3:p.Asn3897fs
  • NP_597681.4:p.Asn3964fs
  • LRG_391:g.94975del
  • NC_000002.11:g.179605555del
  • NC_000002.11:g.179605555delA
  • NM_001256850.1:c.11454delT
  • NM_003319.4:c.11316delT
  • NM_133432.3:c.11691delT
  • p.Asn3897LysfsX33
  • p.N3818KfsX33
Protein change:
N3772fs
Links:
dbSNP: rs727503658
NCBI 1000 Genomes Browser:
rs727503658
Molecular consequence:
  • NM_001256850.1:c.11454del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001267550.2:c.12405del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_003319.4:c.11316del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133432.3:c.11691del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133437.4:c.11892del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133378.4:c.10361-2468del - intron variant - [Sequence Ontology: SO:0001627]
Observations:
1

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000736757Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Feb 2, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Details of each submission

From Ambry Genetics, SCV000736757.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.11316delT variant, located in coding exon 44 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 11316, causing a translational frameshift with a predicted alternate stop codon (p.N3772Kfs*33). 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%). 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 Jan;49:46-53). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Jul 29, 2021

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