NM_001267550.2(TTN):c.26528C>T (p.Thr8843Met) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Jun 28, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000040052.9

Allele description [Variation Report for NM_001267550.2(TTN):c.26528C>T (p.Thr8843Met)]

NM_001267550.2(TTN):c.26528C>T (p.Thr8843Met)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.26528C>T (p.Thr8843Met)
Other names:
p.T8526M:ACG>ATG
HGVS:
  • NC_000002.12:g.178714130G>A
  • NG_011618.3:g.121673C>T
  • NM_001256850.1:c.25577C>T
  • NM_001267550.2:c.26528C>TMANE SELECT
  • NM_003319.4:c.13282+23952C>T
  • NM_133378.4:c.22796C>T
  • NM_133432.3:c.13657+23952C>T
  • NM_133437.4:c.13858+23952C>T
  • NP_001243779.1:p.Thr8526Met
  • NP_001254479.2:p.Thr8843Met
  • NP_596869.4:p.Thr7599Met
  • LRG_391t1:c.26528C>T
  • LRG_391:g.121673C>T
  • NC_000002.11:g.179578857G>A
  • NM_001267550.1:c.26528C>T
  • c.22796C>T
Protein change:
T7599M
Links:
dbSNP: rs72648990
NCBI 1000 Genomes Browser:
rs72648990
Molecular consequence:
  • NM_003319.4:c.13282+23952C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133432.3:c.13657+23952C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133437.4:c.13858+23952C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001256850.1:c.25577C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001267550.2:c.26528C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133378.4:c.22796C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
6

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
SCV000063743Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Uncertain significance
(Jun 28, 2017)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided66not providednot providednot providedclinical testing

Citations

PubMed

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.

Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, Bowser M, Harrison B, Aaron D, Mahanta LM, Lakdawala NK, McDermott G, White ET, Rehm HL, Lebo M, Funke BH.

Genet Med. 2014 Aug;16(8):601-8. doi: 10.1038/gim.2013.204. Epub 2014 Feb 6.

PubMed [citation]
PMID:
24503780

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, SCV000063743.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided6not providednot providedclinical testing PubMed (2)

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Thr7599Met va riant in TTN has been identified by our laboratory in 1 Asian adult with HCM, 1 Ethiopian neonate with congenital HCM, and 2 Caucasian adults with DCM, of which 1 carried a likely pathogenic variant in another gene sufficient to explain the ir disease (Pugh 2014). Additionally, this variant has been identified in 0.1% ( 38/34342) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org/; dbSNP rs72648990) and has been reported in ClinVa r (Variation ID: 46782). Threonine (Thr) at position 7599 is not conserved in ma mmals or evolutionarily distant species, and one mammal (white rhinoceros) carri es a methionine (Met) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools do not provide stro ng support for or against an impact to the protein. In summary, while the clinic al significance of the p.Thr7599Met variant is uncertain, its frequency and lack of conservation suggest that it is more likely to be benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided6not provided6not provided

Last Updated: Sep 6, 2021

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