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NM_003319.4(TTN):c.22101_22120del (p.Val7368fs) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 18, 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:
RCV002426755.2

Allele description [Variation Report for NM_003319.4(TTN):c.22101_22120del (p.Val7368fs)]

NM_003319.4(TTN):c.22101_22120del (p.Val7368fs)

Genes:
TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_003319.4(TTN):c.22101_22120del (p.Val7368fs)
HGVS:
  • NC_000002.12:g.178614084_178614103del
  • NG_011618.3:g.221702_221721del
  • NG_051363.1:g.96258_96277del
  • NM_001256850.1:c.44373_44392del
  • NM_001267550.2:c.49296_49315delMANE SELECT
  • NM_003319.4:c.22101_22120del
  • NM_133378.4:c.41592_41611del
  • NM_133432.3:c.22476_22495del
  • NM_133437.4:c.22677_22696del
  • NP_001243779.1:p.Val14792fs
  • NP_001254479.2:p.Val16433fs
  • NP_003310.4:p.Val7368fs
  • NP_596869.4:p.Val13865fs
  • NP_597676.3:p.Val7493fs
  • NP_597681.4:p.Val7560fs
  • LRG_391:g.221702_221721del
  • NC_000002.11:g.179478811_179478830del
  • NM_003319.4:c.22101_22120del20
  • NR_038271.1:n.832_851del
  • p.Val13865LeufsX10
Protein change:
V13865fs
Links:
dbSNP: rs727504825
NCBI 1000 Genomes Browser:
rs727504825
Molecular consequence:
  • NM_133378.4:c.41592_41611del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002728303Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Dec 18, 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, SCV002728303.2

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

Description

The c.22101_22120del20 variant, located in coding exon 89 of the TTN gene, results from a deletion of 20 nucleotides at nucleotide positions 22101 to 22120, causing a translational frameshift with a predicted alternate stop codon (p.V7368Lfs*10). This exon 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%). While truncating variants in TTN are present in 1-3% of the general population, truncating 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). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

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

Last Updated: Mar 5, 2025