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NM_001267550.2(TTN):c.106114_106115dup (p.Leu35372fs) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 4, 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:
RCV003166256.2

Allele description [Variation Report for NM_001267550.2(TTN):c.106114_106115dup (p.Leu35372fs)]

NM_001267550.2(TTN):c.106114_106115dup (p.Leu35372fs)

Genes:
LOC129935182:ATAC-STARR-seq lymphoblastoid active region 16807 [Gene]
TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.106114_106115dup (p.Leu35372fs)
HGVS:
  • NC_000002.12:g.178530500_178530501dup
  • NG_011618.3:g.305302_305303dup
  • NG_051363.1:g.12674_12675dup
  • NM_001256850.1:c.101191_101192dup
  • NM_001267550.2:c.106114_106115dupMANE SELECT
  • NM_003319.4:c.78919_78920dup
  • NM_133378.4:c.98410_98411dup
  • NM_133432.3:c.79294_79295dup
  • NM_133437.4:c.79495_79496dup
  • NP_001243779.1:p.Leu33731fs
  • NP_001254479.2:p.Leu35372fs
  • NP_003310.4:p.Leu26307fs
  • NP_596869.4:p.Leu32804fs
  • NP_597676.3:p.Leu26432fs
  • NP_597681.4:p.Leu26499fs
  • LRG_391:g.305302_305303dup
  • NC_000002.11:g.179395226_179395227insAA
  • NC_000002.11:g.179395227_179395228dup
  • NM_001267550.2:c.106114_106115dupTTMANE SELECT
  • NM_003319.4:c.78919_78920dupTT
Protein change:
L26307fs
Links:
dbSNP: rs1394131775
NCBI 1000 Genomes Browser:
rs1394131775
Molecular consequence:
  • NM_001256850.1:c.101191_101192dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001267550.2:c.106114_106115dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_003319.4:c.78919_78920dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133378.4:c.98410_98411dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133432.3:c.79294_79295dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133437.4:c.79495_79496dup - 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
SCV003856850Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jan 4, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy.

Goli R, Li J, Brandimarto J, Levine LD, Riis V, McAfee Q, DePalma S, Haghighi A, Seidman JG, Seidman CE, Jacoby D, Macones G, Judge DP, Rana S, Margulies KB, Cappola TP, Alharethi R, Damp J, Hsich E, Elkayam U, Sheppard R, Alexis JD, et al.

Circulation. 2021 May 11;143(19):1852-1862. doi: 10.1161/CIRCULATIONAHA.120.052395. Epub 2021 Apr 20.

PubMed [citation]
PMID:
33874732
PMCID:
PMC8113098

Details of each submission

From Ambry Genetics, SCV003856850.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The c.78919_78920dupTT variant, located in coding exon 185 of the TTN gene, results from a duplication of TT at nucleotide position 78919, causing a translational frameshift with a predicted alternate stop codon (p.L26307Ffs*34). This exon is located in the M-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 (referred to as c.106114_106115dupTT, p.Leu35372fs) has been detected in a peripartum cardiomyopathy cohort; however, details were limited (Goli R et al. Circulation, 2021 May;143:1852-1862). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though truncating variants in the A-band are the most common cause of 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; Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear.

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

Last Updated: Sep 29, 2024