NM_001267550.2(TTN):c.197C>T (p.Thr66Met) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: May 10, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000613481.2

Allele description [Variation Report for NM_001267550.2(TTN):c.197C>T (p.Thr66Met)]

NM_001267550.2(TTN):c.197C>T (p.Thr66Met)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.197C>T (p.Thr66Met)
HGVS:
  • NC_000002.12:g.178802236G>A
  • NG_011618.3:g.33567C>T
  • NM_001256850.1:c.197C>T
  • NM_001267550.2:c.197C>TMANE SELECT
  • NM_003319.4:c.197C>T
  • NM_133378.4:c.197C>T
  • NM_133379.5:c.197C>T
  • NM_133432.3:c.197C>T
  • NM_133437.4:c.197C>T
  • NP_001243779.1:p.Thr66Met
  • NP_001254479.2:p.Thr66Met
  • NP_003310.4:p.Thr66Met
  • NP_596869.4:p.Thr66Met
  • NP_596870.2:p.Thr66Met
  • NP_597676.3:p.Thr66Met
  • NP_597681.4:p.Thr66Met
  • LRG_391:g.33567C>T
  • NC_000002.11:g.179666963G>A
Protein change:
T66M
Links:
dbSNP: rs372755739
NCBI 1000 Genomes Browser:
rs372755739
Molecular consequence:
  • NM_001256850.1:c.197C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001267550.2:c.197C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003319.4:c.197C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133378.4:c.197C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133379.5:c.197C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133432.3:c.197C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133437.4:c.197C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000719637GeneDxcriteria provided, single submitter
Likely benign
(May 16, 2017)
germlineclinical testing

Citation Link,

SCV001623242Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(May 10, 2021)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000719637.1

#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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623242.1

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

Description

Variant summary: TTN c.197C>T (p.Thr66Met) results in a non-conservative amino acid change located in the Z-disk region (cardiodb.org) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251316 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (4.4e-05 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.197C>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Last Updated: Nov 27, 2021

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