NM_001267550.2(TTN):c.40963G>T (p.Glu13655Ter) AND multiple conditions

Clinical significance:Uncertain significance (Last evaluated: Apr 30, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000560235.5

Allele description [Variation Report for NM_001267550.2(TTN):c.40963G>T (p.Glu13655Ter)]

NM_001267550.2(TTN):c.40963G>T (p.Glu13655Ter)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.40963G>T (p.Glu13655Ter)
HGVS:
  • NC_000002.12:g.178636764C>A
  • NG_011618.3:g.199039G>T
  • NM_001256850.1:c.36040G>T
  • NM_001267550.2:c.40963G>TMANE SELECT
  • NM_003319.4:c.13768G>T
  • NM_133378.4:c.33259G>T
  • NM_133432.3:c.14143G>T
  • NM_133437.4:c.14344G>T
  • NP_001243779.1:p.Glu12014Ter
  • NP_001254479.2:p.Glu13655Ter
  • NP_003310.4:p.Glu4590Ter
  • NP_596869.4:p.Glu11087Ter
  • NP_597676.3:p.Glu4715Ter
  • NP_597681.4:p.Glu4782Ter
  • LRG_391:g.199039G>T
  • NC_000002.11:g.179501491C>A
  • NP_596869.4:p.Glu11087*
Protein change:
E11087*
Links:
dbSNP: rs727504198
NCBI 1000 Genomes Browser:
rs727504198
Molecular consequence:
  • NM_001256850.1:c.36040G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001267550.2:c.40963G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_003319.4:c.13768G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133378.4:c.33259G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133432.3:c.14143G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133437.4:c.14344G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Dilated cardiomyopathy 1G (CMD1G)
Identifiers:
MONDO: MONDO:0011400; MedGen: C1858763; Orphanet: 154; OMIM: 604145
Name:
Limb-girdle muscular dystrophy, type 2J (LGMDR10)
Synonyms:
MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 10
Identifiers:
MONDO: MONDO:0012127; MedGen: C1837342; Orphanet: 140922; OMIM: 608807

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000643133Invitaecriteria provided, single submitter
Uncertain significance
(Apr 30, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, et al.

Sci Transl Med. 2015 Jan 14;7(270):270ra6. doi: 10.1126/scitranslmed.3010134.

PubMed [citation]
PMID:
25589632
PMCID:
PMC4560092

Prevalence of Titin Truncating Variants in General Population.

Akinrinade O, Koskenvuo JW, Alastalo TP.

PLoS One. 2015;10(12):e0145284. doi: 10.1371/journal.pone.0145284.

PubMed [citation]
PMID:
26701604
PMCID:
PMC4689403
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000643133.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change results in a premature translational stop signal in the TTN gene (p.Glu13655*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of congenital myopathy (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 167788). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Apr 12, 2021

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