NM_001267550.2(TTN):c.59926+1G>C AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 19, 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:: RCV003780137.2

Allele description [Variation Report for NM_001267550.2(TTN):c.59926+1G>C]

NM_001267550.2(TTN):c.59926+1G>C

Genes:

LOC126806424:CDK7 strongly-dependent group 2 enhancer GRCh37_chr2:179456337-179457536 [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.59926+1G>C

HGVS:

NC_000002.12:g.178591977C>G
NG_011618.3:g.243826G>C
NG_051363.1:g.74151C>G
NG_082744.1:g.468C>G
NM_001256850.1:c.55003+1G>C
NM_001267550.2:c.59926+1G>CMANE SELECT
NM_003319.4:c.32731+1G>C
NM_133378.4:c.52222+1G>C
NM_133432.3:c.33106+1G>C
NM_133437.4:c.33307+1G>C
LRG_391:g.243826G>C
NC_000002.11:g.179456704C>G

Molecular consequence:

NM_001256850.1:c.55003+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001267550.2:c.59926+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_003319.4:c.32731+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_133378.4:c.52222+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_133432.3:c.33106+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_133437.4:c.33307+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV004604035	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22335739, 29057560, 25589632, 23975875, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004604035

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 19, 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

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

The first titin (c.59926 + 1G > A) founder mutation associated with dilated cardiomyopathy.

Hoorntje ET, van Spaendonck-Zwarts KY, Te Rijdt WP, Boven L, Vink A, van der Smagt JJ, Asselbergs FW, van Wijngaarden J, Hennekam EA, Pinto YM, Lekanne Deprez RH, Barge-Schaapveld DQCM, Bootsma M, Regieli J, Hoedemaekers YM, Jongbloed JDH, van den Berg MP, van Tintelen JP.

Eur J Heart Fail. 2018 Apr;20(4):803-806. doi: 10.1002/ejhf.1030. Epub 2017 Oct 23. No abstract available.

PubMed [citation]

PMID:: 29057560
PMCID:: PMC5993291

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004604035.1

#	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 affects a donor splice site in intron 302 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 22335739, 29057560). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: Sep 29, 2024

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