NM_001267550.2(TTN):c.12519_12520del (p.Glu4173fs) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 4, 2017
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:: RCV000642816.6

Allele description [Variation Report for NM_001267550.2(TTN):c.12519_12520del (p.Glu4173fs)]

NM_001267550.2(TTN):c.12519_12520del (p.Glu4173fs)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.12519_12520del (p.Glu4173fs)

HGVS:

NC_000002.12:g.178740713TC[1]
NG_011618.3:g.95087GA[1]
NM_001256850.1:c.11568_11569del
NM_001267550.2:c.12519_12520delMANE SELECT
NM_003319.4:c.11430_11431del
NM_133378.4:c.10361-2354_10361-2353del
NM_133432.3:c.11805_11806del
NM_133437.4:c.12006_12007del
NP_001243779.1:p.Glu3856fs
NP_001254479.2:p.Glu4173fs
NP_003310.4:p.Glu3810fs
NP_597676.3:p.Glu3935fs
NP_597681.4:p.Glu4002fs
LRG_391:g.95087GA[1]
NC_000002.11:g.179605440TC[1]
NC_000002.11:g.179605440_179605441del
NM_001267550.2:c.12519_12520delGAMANE SELECT

Protein change:

E3810fs

Links:

dbSNP: rs1553939605

NCBI 1000 Genomes Browser:

rs1553939605

Molecular consequence:

NM_001256850.1:c.11568_11569del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001267550.2:c.12519_12520del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003319.4:c.11430_11431del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133432.3:c.11805_11806del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133437.4:c.12006_12007del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133378.4:c.10361-2354_10361-2353del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000764503	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 4, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26701604, 22335739, 23975875, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000764503

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 4, 2017)

germline

clinical testing

PubMed (4)
[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

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

Truncations of titin causing dilated cardiomyopathy.

Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, et al.

N Engl J Med. 2012 Feb 16;366(7):619-28. doi: 10.1056/NEJMoa1110186.

PubMed [citation]

PMID:: 22335739
PMCID:: PMC3660031

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000764503.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, although this is a novel truncating variant, truncating variants in this region of the TTN gene have been shown to be highly prevalent in the TTN gene in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating mutations in this region have also been reported to cause autosomal recessive congenital myopathy (PMID: 23975875). Therefore without additional functional and/or genetic data, this variant has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with TTN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TTN gene (p.Glu4173Aspfs*22). 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: Apr 6, 2024

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