NM_001267550.2(TTN):c.583+5G>A AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(2) (Last evaluated: Oct 1, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000040502.4

Allele description [Variation Report for NM_001267550.2(TTN):c.583+5G>A]

NM_001267550.2(TTN):c.583+5G>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.583+5G>A
HGVS:
  • NC_000002.12:g.178800390C>T
  • NG_011618.3:g.35413G>A
  • NM_001256850.1:c.583+5G>A
  • NM_001267550.2:c.583+5G>AMANE SELECT
  • NM_003319.4:c.583+5G>A
  • NM_133378.4:c.583+5G>A
  • NM_133379.5:c.583+5G>A
  • NM_133432.3:c.583+5G>A
  • NM_133437.4:c.583+5G>A
  • LRG_391:g.35413G>A
  • NC_000002.11:g.179665117C>T
  • c.583+5G>A
Links:
dbSNP: rs397517663
NCBI 1000 Genomes Browser:
rs397517663
Molecular consequence:
  • NM_001256850.1:c.583+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001267550.2:c.583+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_003319.4:c.583+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133378.4:c.583+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133379.5:c.583+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133432.3:c.583+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133437.4:c.583+5G>A - intron variant - [Sequence Ontology: SO:0001627]
Observations:
2

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000064193Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Uncertain significance
(Jul 23, 2014)
germlineclinical testing

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

SCV000727069GeneDxcriteria provided, single submitter
Likely benign
(Jan 25, 2018)
germlineclinical testing

Citation Link,

SCV001159937ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(Oct 1, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided22not providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000064193.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (1)

Description

The 583+5G>A variant in TTN has been identified by our laboratory in 1 Black ind ividual with LVNC. It was absent from large population studies. This variant is located in the 5' splice region. Computational tools suggest a possible impact t o splicing; however, this information is not predictive enough to determine path ogenicity. In summary, the clinical significance of the 583+5G>A variant is unce rtain.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not provided2not provided

From GeneDx, SCV000727069.1

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001159937.1

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

Description

The TTN c.583+5G>A variant (rs397517663), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 47232). This variant is found on three chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical splice donor site, though mRNA studies would be required to confirm an effect on splicing. Given the lack of clinical and functional data, the significance of the c.583+5G>A variant is uncertain at this time.

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

Last Updated: Aug 25, 2021

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