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NM_001267550.2(TTN):c.10241_10247delACACGTT (p.Tyr3414Leufs) AND Primary dilated cardiomyopathy

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jun 25, 2015
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:
RCV000214597.1

Allele description

NM_001267550.2(TTN):c.10241_10247delACACGTT (p.Tyr3414Leufs)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.10241_10247delACACGTT (p.Tyr3414Leufs)
HGVS:
  • NC_000002.12:g.178759040_178759046delAACGTGT
  • NG_011618.3:g.76757_76763delACACGTT
  • NM_001267550.2:c.10241_10247delACACGTT
  • NM_133378.4:c.10241_10247delACACGTT
  • NM_133379.4:c.10241_10247delACACGTT
  • NP_001254479.2:p.Tyr3414Leufs
  • NP_596869.4:p.Tyr3414Leufs
  • NP_596870.2:p.Tyr3414Leufs
  • LRG_391t2:c.10241_10247delACACGTT
  • LRG_391:g.76757_76763delACACGTT
  • LRG_391p2:p.Tyr3414Leufs
  • NC_000002.11:g.179623767_179623773delAACGTGT
  • p.Tyr3414LeufsX7
Links:
dbSNP: rs876657663
NCBI 1000 Genomes Browser:
rs876657663
Molecular consequence:
  • NM_001267550.2:c.10241_10247delACACGTT - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
1

Condition(s)

Name:
Primary dilated cardiomyopathy (DCM)
Synonyms:
Congestive cardiomyopathy
Identifiers:
EFO: EFO_0000407; MedGen: C0007193; Human Phenotype Ontology: HP:0001644

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000271273Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Likely pathogenic
(Jun 25, 2015) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Details of each submission

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000271273.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The p.Tyr3414fs variant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies, though the ability of these studies to accurately detect deletions may be limited. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3414 and leads to a premature termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (Herman 2012, Pugh 2014) or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Tyr3414fs variant is located in the I-band in the highly expressed exon 44. In summary, although additional studies are required to fully establish its clinical significance, the p.Tyr3414fs variant is likely pathogenic.

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

Last Updated: Apr 2, 2018