NM_001267550.2(TTN):c.49171C>T (p.Arg16391Ter) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 17, 2024
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:: RCV001069013.5

Allele description [Variation Report for NM_001267550.2(TTN):c.49171C>T (p.Arg16391Ter)]

NM_001267550.2(TTN):c.49171C>T (p.Arg16391Ter)

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:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.49171C>T (p.Arg16391Ter)

HGVS:

NC_000002.12:g.178614226G>A
NG_011618.3:g.221577C>T
NG_051363.1:g.96400G>A
NM_001256850.1:c.44248C>T
NM_001267550.2:c.49171C>TMANE SELECT
NM_003319.4:c.21976C>T
NM_133378.4:c.41467C>T
NM_133432.3:c.22351C>T
NM_133437.4:c.22552C>T
NP_001243779.1:p.Arg14750Ter
NP_001254479.2:p.Arg16391Ter
NP_003310.4:p.Arg7326Ter
NP_596869.4:p.Arg13823Ter
NP_597676.3:p.Arg7451Ter
NP_597681.4:p.Arg7518Ter
LRG_391t1:c.49171C>T
LRG_391:g.221577C>T
NC_000002.11:g.179478953G>A
NM_001267550.1:c.49171C>T
NM_003319.4:c.21976C>T
NR_038271.1:n.974G>A

Protein change:

R13823*

Links:

dbSNP: rs570046043

NCBI 1000 Genomes Browser:

rs570046043

Molecular consequence:

NR_038271.1:n.974G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001256850.1:c.44248C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001267550.2:c.49171C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003319.4:c.21976C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133378.4:c.41467C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133432.3:c.22351C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133437.4:c.22552C>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
SCV001234156	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30471092, 31737537, 34088380, 25589632, 23975875, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001234156

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 17, 2024)

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

Targeted panel sequencing in adult patients with left ventricular non-compaction reveals a large genetic heterogeneity.

Richard P, Ader F, Roux M, Donal E, Eicher JC, Aoutil N, Huttin O, Selton-Suty C, Coisne D, Jondeau G, Damy T, Mansencal N, Casalta AC, Michel N, Haentjens J, Faivre L, Lavoute C, Nguyen K, Tregouët DA, Habib G, Charron P.

Clin Genet. 2019 Mar;95(3):356-367. doi: 10.1111/cge.13484. Epub 2018 Dec 27.

PubMed [citation]

PMID:: 30471092

Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders.

Marschall C, Moscu-Gregor A, Klein HG.

Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298. doi: 10.21037/cdt.2019.06.06.

PubMed [citation]

PMID:: 31737537
PMCID:: PMC6837920

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001234156.5

#	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.Arg16391*) 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 premature translational stop signal has been observed in individual(s) with left ventricular non-compaction or dilated cardiomyopathy (PMID: 30471092, 31737537, 34088380). This variant is also known as p.Arg14750X. ClinVar contains an entry for this variant (Variation ID: 636978). 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.

#	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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