NM_001267550.2(TTN):c.41937del (p.Glu13980fs) AND multiple conditions

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 14, 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:: RCV003813084.1

Allele description

NM_001267550.2(TTN):c.41937del (p.Glu13980fs)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.41937del (p.Glu13980fs)

HGVS:

NC_000002.12:g.178635254del
NG_011618.3:g.200551del
NM_001256850.1:c.37014del
NM_001267550.2:c.41937delMANE SELECT
NM_003319.4:c.14742del
NM_133378.4:c.34233del
NM_133432.3:c.15117del
NM_133437.4:c.15318del
NP_001243779.1:p.Glu12339fs
NP_001254479.1:p.Glu13980Lysfs
NP_001254479.2:p.Glu13980fs
NP_003310.4:p.Glu4915fs
NP_596869.4:p.Glu11412fs
NP_597676.3:p.Glu5040fs
NP_597681.4:p.Glu5107fs
LRG_391t1:c.41935del
LRG_391:g.200551del
LRG_391p1:p.Glu13980Lysfs
NC_000002.11:g.179499979del
NC_000002.11:g.179499981del
NM_001267550.1:c.41935delA

Protein change:

E11412fs

Molecular consequence:

NM_001256850.1:c.37014del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001267550.2:c.41937del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003319.4:c.14742del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133378.4:c.34233del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133432.3:c.15117del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133437.4:c.15318del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004609456	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 14, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25589632, 23975875, 27869827, 32964742, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004609456

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 14, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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, SCV004609456.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Glu13980Lysfs*20) 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 variant has not been reported in the literature in individuals affected with TTN-related conditions. 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). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 5, 2024

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