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NM_001267550.2(TTN):c.52551del (p.Arg17518fs) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 29, 2021
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:
RCV002953805.4

Allele description [Variation Report for NM_001267550.2(TTN):c.52551del (p.Arg17518fs)]

NM_001267550.2(TTN):c.52551del (p.Arg17518fs)

Genes:
LOC126806425:BRD4-independent group 4 enhancer GRCh37_chr2:179471933-179473132 [Gene]
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.52551del (p.Arg17518fs)
HGVS:
  • NC_000002.12:g.178608332del
  • NG_011618.3:g.227471del
  • NG_051363.1:g.90506del
  • NG_082745.1:g.1227del
  • NM_001256850.1:c.47628del
  • NM_001267550.2:c.52551delMANE SELECT
  • NM_003319.4:c.25356del
  • NM_133378.4:c.44847del
  • NM_133432.3:c.25731del
  • NM_133437.4:c.25932del
  • NP_001243779.1:p.Arg15877fs
  • NP_001254479.1:p.Arg17518Valfs
  • NP_001254479.2:p.Arg17518fs
  • NP_003310.4:p.Arg8453fs
  • NP_596869.4:p.Arg14950fs
  • NP_597676.3:p.Arg8578fs
  • NP_597681.4:p.Arg8645fs
  • LRG_391t1:c.52551del
  • LRG_391:g.227471del
  • LRG_391p1:p.Arg17518Valfs
  • NC_000002.11:g.179473059del
  • NM_001267550.1:c.52551delT
Protein change:
R14950fs
Links:
dbSNP: rs2470330946
NCBI 1000 Genomes Browser:
rs2470330946
Molecular consequence:
  • NM_001256850.1:c.47628del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001267550.2:c.52551del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_003319.4:c.25356del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133378.4:c.44847del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133432.3:c.25731del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133437.4:c.25932del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV003275737Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Dec 29, 2021) 		germlineclinical testing

PubMed (3)
[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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003275737.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg17518Valfs*7) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.

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

Last Updated: May 16, 2025