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NM_001267550.2(TTN):c.2371-1G>A AND Cardiovascular phenotype

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Nov 9, 2018
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:
RCV002422611.2

Allele description [Variation Report for NM_001267550.2(TTN):c.2371-1G>A]

NM_001267550.2(TTN):c.2371-1G>A

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.2371-1G>A
HGVS:
  • NC_000002.12:g.178785743C>T
  • NG_011618.3:g.50060G>A
  • NM_001256850.1:c.2371-1G>A
  • NM_001267550.2:c.2371-1G>AMANE SELECT
  • NM_003319.4:c.2233-1G>A
  • NM_133378.4:c.2371-1G>A
  • NM_133379.5:c.2371-1G>A
  • NM_133432.3:c.2233-1G>A
  • NM_133437.4:c.2233-1G>A
  • LRG_391:g.50060G>A
  • NC_000002.11:g.179650470C>T
  • NM_003319.4:c.2233-1G>A
Links:
dbSNP: rs755365744
NCBI 1000 Genomes Browser:
rs755365744
Molecular consequence:
  • NM_001256850.1:c.2371-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001267550.2:c.2371-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_003319.4:c.2233-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_133378.4:c.2371-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_133379.5:c.2371-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_133432.3:c.2233-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_133437.4:c.2233-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002725414Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Nov 9, 2018) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Ambry Genetics, SCV002725414.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The c.2233-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 13 of the TTN gene. Exon 13 is located in the Z-disk region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 99%). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site. Although direct evidence is unavailable, this variant disrupts the canonical acceptor splice site of exon 13 and is expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. While loss of function variants in TTN are present in 1-3% of the general population, truncating variants (a category that includes canonical splice site variants) in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med. 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med. 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet. 2017 Jan;49:46-53). However, since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024