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NM_001267550.2(TTN):c.69571_69592dup (p.Arg23198fs) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 12, 2022
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:
RCV003170538.2

Allele description [Variation Report for NM_001267550.2(TTN):c.69571_69592dup (p.Arg23198fs)]

NM_001267550.2(TTN):c.69571_69592dup (p.Arg23198fs)

Genes:
LOC126806422:BRD4-independent group 4 enhancer GRCh37_chr2:179440205-179441404 [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.69571_69592dup (p.Arg23198fs)
HGVS:
  • NC_000002.12:g.178576653_178576674dup
  • NG_011618.3:g.259130_259151dup
  • NG_051363.1:g.58827_58848dup
  • NM_001256850.1:c.64648_64669dup
  • NM_001267550.2:c.69571_69592dupMANE SELECT
  • NM_003319.4:c.42376_42397dup
  • NM_133378.4:c.61867_61888dup
  • NM_133432.3:c.42751_42772dup
  • NM_133437.4:c.42952_42973dup
  • NP_001243779.1:p.Arg21557fs
  • NP_001254479.2:p.Arg23198fs
  • NP_003310.4:p.Arg14133fs
  • NP_596869.4:p.Arg20630fs
  • NP_597676.3:p.Arg14258fs
  • NP_597681.4:p.Arg14325fs
  • LRG_391:g.259130_259151dup
  • NC_000002.11:g.179441378_179441379insTGAGATCGGAAACTGGTGTTTT
  • NC_000002.11:g.179441380_179441401dup
  • NM_003319.4:c.42376_42397dupAAAACACCAGTTTCCGATCTCA
Protein change:
R14133fs
Links:
dbSNP: rs2046499843
NCBI 1000 Genomes Browser:
rs2046499843
Molecular consequence:
  • NM_001256850.1:c.64648_64669dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001267550.2:c.69571_69592dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_003319.4:c.42376_42397dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133378.4:c.61867_61888dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133432.3:c.42751_42772dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133437.4:c.42952_42973dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV003856815Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Likely pathogenic
(Dec 12, 2022)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From Ambry Genetics, SCV003856815.2

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

Description

The c.42376_42397dup22 variant, located in coding exon 152 of the TTN gene, results from a duplication of AAAACACCAGTTTCCGATCTCA at nucleotide position 42376, causing a translational frameshift with a predicted alternate stop codon (p.R14133Kfs*37). 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%). 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 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 01;49:46-53). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Sep 29, 2024