NM_001256850.1(TTN):c.39893-1G>A AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Apr 23, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000184214.6

Allele description [Variation Report for NM_001256850.1(TTN):c.39893-1G>A]

NM_001256850.1(TTN):c.39893-1G>A

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001256850.1(TTN):c.39893-1G>A
Other names:
IVS192-1 G>A
HGVS:
  • NC_000002.12:g.178622768C>T
  • NG_011618.3:g.213035G>A
  • NM_001256850.1:c.39893-1G>A
  • NM_001267550.2:c.44816-1G>AMANE SELECT
  • NM_003319.4:c.17621-1G>A
  • NM_133378.4:c.37112-1G>A
  • NM_133432.3:c.17996-1G>A
  • NM_133437.4:c.18197-1G>A
  • LRG_391:g.213035G>A
  • NC_000002.11:g.179487495C>T
Links:
dbSNP: rs749705939
NCBI 1000 Genomes Browser:
rs749705939
Molecular consequence:
  • NM_001256850.1:c.39893-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001267550.2:c.44816-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_003319.4:c.17621-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_133378.4:c.37112-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_133432.3:c.17996-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_133437.4:c.18197-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
Observations:
1

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000236836GeneDxcriteria provided, single submitter
Pathogenic
(Apr 23, 2018)
germlineclinical testing

Citation Link,

SCV000338272EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Uncertain significance
(Mar 9, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown1not providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000236836.10

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

Description

The c.39893-1 G>A pathogenic variant in the TTN gene has been reported in a patient with centronuclear myopathy and a normal cardiac evaluation who also harbored c.35635 G>C in the TTN gene in trans (Ceyhan-Birsoy et al., 2013). The c.39893-1 G>A variant was maternally inherited from a mother with subclinical cardiac and skeletal myopathies (Ceyhan-Birsoy et al., 2013). This variant has also been identified in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and was found to segregate with disease in multiple affected individuals from two unrelated families. The c.39893-1 G>A variant destroys the canonical splice acceptor site in intron 192 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Immunofluorescence analysis on a muscle biopsy from a patient harboring c.39893-1 G>A demonstrated truncated protein product (Ceyhan-Birsoy et al., 2013). Truncating TTN variants have been reported in approximately 3% of control alleles, and the majority of truncating pathogenic variants associated with DCM have been reported in the A-band (Herman et al., 2012). However, the c.39893-1 G>A variant is located in one of the constitutive exons in the distal I-band region, and recent studies suggest that truncating variants affecting constitutive exons throughout the TTN gene are also significantly associated with DCM (Rahual C. Deo, 2016; Schafer et al., 2017). Furthermore, the c.39893-1 G>A variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016).

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

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000338272.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

Last Updated: May 10, 2021

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