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NM_001267550.2(TTN):c.34253_34277del (p.Leu11418fs) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 11, 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:
RCV000530661.8

Allele description [Variation Report for NM_001267550.2(TTN):c.34253_34277del (p.Leu11418fs)]

NM_001267550.2(TTN):c.34253_34277del (p.Leu11418fs)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.34253_34277del (p.Leu11418fs)
HGVS:
  • NC_000002.12:g.178677637_178677661del
  • NG_011618.3:g.158144_158168del
  • NM_001256850.1:c.33302_33326del
  • NM_001267550.2:c.34253_34277delMANE SELECT
  • NM_003319.4:c.13283-35342_13283-35318del
  • NM_133378.4:c.30521_30545del
  • NM_133432.3:c.13658-35342_13658-35318del
  • NM_133437.4:c.13859-35342_13859-35318del
  • NP_001243779.1:p.Leu11101fs
  • NP_001254479.2:p.Leu11418fs
  • NP_596869.4:p.Leu10174fs
  • LRG_391:g.158144_158168del
  • NC_000002.11:g.179542362_179542386del
  • NC_000002.11:g.179542364_179542388del
  • NM_001267550.2:c.34253_34277delTTCCAGAAGTTAAACCTAAGGTGCCMANE SELECT
Protein change:
L10174fs
Links:
dbSNP: rs1373610867
NCBI 1000 Genomes Browser:
rs1373610867
Molecular consequence:
  • NM_001256850.1:c.33302_33326del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001267550.2:c.34253_34277del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133378.4:c.30521_30545del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_003319.4:c.13283-35342_13283-35318del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133432.3:c.13658-35342_13658-35318del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133437.4:c.13859-35342_13859-35318del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Dilated cardiomyopathy 1G (CMD1G)
Identifiers:
MONDO: MONDO:0011400; MedGen: C1858763; Orphanet: 154; OMIM: 604145
Name:
Autosomal recessive limb-girdle muscular dystrophy type 2J (LGMDR10)
Synonyms:
Limb-girdle muscular dystrophy, type 2J; 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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000643022Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 11, 2023) 		germlineclinical testing

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

Help

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

Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy.

Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, Schmitz-Abe K, DeChene ET, Swanson LC, Soemedi R, Vasli N, Iannaccone ST, Shieh PB, Shur N, Dennison JM, Lawlor MW, Laporte J, Markianos K, Fairbrother WG, Granzier H, Beggs AH.

Neurology. 2013 Oct 1;81(14):1205-14. doi: 10.1212/WNL.0b013e3182a6ca62. Epub 2013 Aug 23.

PubMed [citation]
PMID:
23975875
PMCID:
PMC3795603
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000643022.7

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

Description

This sequence change creates a premature translational stop signal (p.Leu11418Glnfs*42) in the TTN gene. 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 (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive TTN-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 467038). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Mar 5, 2024