NM_001267550.2(TTN):c.49187_49191dup (p.Trp16398fs) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 26, 2022
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:: RCV003027853.3

Allele description [Variation Report for NM_001267550.2(TTN):c.49187_49191dup (p.Trp16398fs)]

NM_001267550.2(TTN):c.49187_49191dup (p.Trp16398fs)

Genes:

LOC126806426:BRD4-independent group 4 enhancer GRCh37_chr2:179478848-179480047 [Gene]
TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.49187_49191dup (p.Trp16398fs)

HGVS:

NC_000002.12:g.178614210_178614214dup
NG_011618.3:g.221593_221597dup
NG_051363.1:g.96384_96388dup
NG_082746.1:g.190_194dup
NM_001256850.1:c.44264_44268dup
NM_001267550.2:c.49187_49191dupMANE SELECT
NM_003319.4:c.21992_21996dup
NM_133378.4:c.41483_41487dup
NM_133432.3:c.22367_22371dup
NM_133437.4:c.22568_22572dup
NP_001243779.1:p.Trp14757fs
NP_001254479.1:p.Trp16398Lysfs
NP_001254479.2:p.Trp16398fs
NP_003310.4:p.Trp7333fs
NP_596869.4:p.Trp13830fs
NP_597676.3:p.Trp7458fs
NP_597681.4:p.Trp7525fs
LRG_391t1:c.49183_49187dup
LRG_391:g.221593_221597dup
LRG_391p1:p.Trp16398Lysfs
NC_000002.11:g.179478932_179478933insCACTT
NC_000002.11:g.179478937_179478941dup
NM_001267550.1:c.49183_49187dup
NR_038271.1:n.958_962dup

Protein change:

W13830fs

Molecular consequence:

NM_001256850.1:c.44264_44268dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001267550.2:c.49187_49191dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003319.4:c.21992_21996dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133378.4:c.41483_41487dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133432.3:c.22367_22371dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133437.4:c.22568_22572dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_038271.1:n.958_962dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV003330651	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 26, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25589632, 23975875, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003330651

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 26, 2022)

germline

clinical testing

PubMed (3)
[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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003330651.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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). 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 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.Trp16398Lysfs*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.

#	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: Sep 29, 2024

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