NM_001267550.2(TTN):c.51436+1G>A AND Cardiovascular phenotype

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 7, 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:: RCV003165413.9

Allele description [Variation Report for NM_001267550.2(TTN):c.51436+1G>A]

NM_001267550.2(TTN):c.51436+1G>A

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.51436+1G>A

HGVS:

NC_000002.12:g.178610089C>T
NG_011618.3:g.225714G>A
NG_051363.1:g.92263C>T
NM_001256850.1:c.46513+1G>A
NM_001267550.2:c.51436+1G>AMANE SELECT
NM_003319.4:c.24241+1G>A
NM_133378.4:c.43732+1G>A
NM_133432.3:c.24616+1G>A
NM_133437.4:c.24817+1G>A
LRG_391t1:c.51436+1G>A
LRG_391:g.225714G>A
NC_000002.11:g.179474816C>T
NM_001267550.1:c.51436+1G>A
NM_003319.4:c.24241+1G>A
NM_133378.4:c.43732+1G>A
NM_133379.3:c.*135496G>A

Links:

dbSNP: rs761807131

NCBI 1000 Genomes Browser:

rs761807131

Molecular consequence:

NM_001256850.1:c.46513+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001267550.2:c.51436+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_003319.4:c.24241+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_133378.4:c.43732+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_133432.3:c.24616+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_133437.4:c.24817+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003858762	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 7, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28135719, 29253866 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003858762

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 7, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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 and architecture of de novo mutations in developmental disorders.

Deciphering Developmental Disorders Study.

Nature. 2017 Feb 23;542(7642):433-438. doi: 10.1038/nature21062. Epub 2017 Jan 25.

PubMed [citation]

PMID:: 28135719
PMCID:: PMC6016744

High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation.

Klauke B, Gaertner-Rommel A, Schulz U, Kassner A, Zu Knyphausen E, Laser T, Kececioglu D, Paluszkiewicz L, Blanz U, Sandica E, van den Bogaerdt AJ, van Tintelen JP, Gummert J, Milting H.

PLoS One. 2017;12(12):e0189489. doi: 10.1371/journal.pone.0189489.

PubMed [citation]

PMID:: 29253866
PMCID:: PMC5734774

Details of each submission

From Ambry Genetics, SCV003858762.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.24241+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 98 of the TTN gene. Exon 98 is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This variant (also referred to as c.51436+1G>A and 2:179474816C>T) has been detected in an individual with dilated cardiomyopathy and in an individual from a developmental disorders cohort (Klauke B et al. PLoS One, 2017 Dec;12:e0189489; McRae JF et al. Nature, 2017 Feb;542:433-438). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration disrupts the canonical splice site and is expected to cause aberrant splicing. However, although direct evidence is unavailable, this alteration is predicted to result in an in-frame transcript that is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the predicted splice impact is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: Mar 16, 2025

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