NM_001267550.2(TTN):c.81527G>T (p.Arg27176Leu) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Aug 17, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000605477.2

Allele description [Variation Report for NM_001267550.2(TTN):c.81527G>T (p.Arg27176Leu)]

NM_001267550.2(TTN):c.81527G>T (p.Arg27176Leu)

Genes:
TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.81527G>T (p.Arg27176Leu)
HGVS:
  • NC_000002.12:g.178564605C>A
  • NG_011618.3:g.271198G>T
  • NG_051363.1:g.46779C>A
  • NM_001256850.1:c.76604G>T
  • NM_001267550.2:c.81527G>TMANE SELECT
  • NM_003319.4:c.54332G>T
  • NM_133378.4:c.73823G>T
  • NM_133432.3:c.54707G>T
  • NM_133437.4:c.54908G>T
  • NP_001243779.1:p.Arg25535Leu
  • NP_001254479.2:p.Arg27176Leu
  • NP_003310.4:p.Arg18111Leu
  • NP_596869.4:p.Arg24608Leu
  • NP_597676.3:p.Arg18236Leu
  • NP_597681.4:p.Arg18303Leu
  • LRG_391:g.271198G>T
  • NC_000002.11:g.179429332C>A
Protein change:
R18111L
Links:
dbSNP: rs199726308
NCBI 1000 Genomes Browser:
rs199726308
Molecular consequence:
  • NM_001256850.1:c.76604G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001267550.2:c.81527G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003319.4:c.54332G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133378.4:c.73823G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133432.3:c.54707G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133437.4:c.54908G>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
SCV000714532GeneDxcriteria provided, single submitter
Likely benign
(Mar 1, 2018)
germlineclinical testing

Citation Link,

SCV001432111Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Aug 17, 2020)
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, SCV000714532.1

#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, SCV001432111.1

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

Description

Variant summary: TTN c.73823G>T (p.Arg24608Leu) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 248196 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00012 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.73823G>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=3). 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: Oct 8, 2021

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