NM_001267550.2(TTN):c.63601C>T (p.Arg21201Ter) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 27, 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:: RCV001239700.8

Allele description [Variation Report for NM_001267550.2(TTN):c.63601C>T (p.Arg21201Ter)]

NM_001267550.2(TTN):c.63601C>T (p.Arg21201Ter)

Genes:

TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.63601C>T (p.Arg21201Ter)

HGVS:

NC_000002.12:g.178587708G>A
NG_011618.3:g.248095C>T
NG_051363.1:g.69882G>A
NM_001256850.1:c.58678C>T
NM_001267550.2:c.63601C>TMANE SELECT
NM_003319.4:c.36406C>T
NM_133378.4:c.55897C>T
NM_133432.3:c.36781C>T
NM_133437.4:c.36982C>T
NP_001243779.1:p.Arg19560Ter
NP_001254479.2:p.Arg21201Ter
NP_003310.4:p.Arg12136Ter
NP_596869.4:p.Arg18633Ter
NP_597676.3:p.Arg12261Ter
NP_597681.4:p.Arg12328Ter
LRG_391t1:c.63601C>T
LRG_391:g.248095C>T
NC_000002.11:g.179452435G>A
NM_001267550.1:c.63601C>T
NM_003319.4:c.36406C>T
NM_133378.4:c.55897C>T

Protein change:

R12136*

Links:

dbSNP: rs764243269

NCBI 1000 Genomes Browser:

rs764243269

Molecular consequence:

NM_001256850.1:c.58678C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001267550.2:c.63601C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003319.4:c.36406C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133378.4:c.55897C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133432.3:c.36781C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133437.4:c.36982C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001412593	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 27, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22335739, 33449170, 33874732, 25589632, 23975875, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001412593

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 27, 2023)

germline

clinical testing

PubMed (6)
[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

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

Making sense of missense variants in TTN-related congenital myopathies.

Rees M, Nikoopour R, Fukuzawa A, Kho AL, Fernandez-Garcia MA, Wraige E, Bodi I, Deshpande C, Özdemir Ö, Daimagüler HS, Pfuhl M, Holt M, Brandmeier B, Grover S, Fluss J, Longman C, Farrugia ME, Matthews E, Hanna M, Muntoni F, Sarkozy A, Phadke R, et al.

Acta Neuropathol. 2021 Mar;141(3):431-453. doi: 10.1007/s00401-020-02257-0. Epub 2021 Jan 15.

PubMed [citation]

PMID:: 33449170
PMCID:: PMC7882473

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001412593.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Arg21201*) 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 present in population databases (rs764243269, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with autosomal dominant and autosomal recessive TTN-related conditions (PMID: 22335739, 33449170, 33874732; Invitae). This variant is also known as c.58678C>T (p.Arg19560X). ClinVar contains an entry for this variant (Variation ID: 223314). 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). For these reasons, this variant has been classified as 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: May 1, 2024

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