NM_001267550.2(TTN):c.90968G>C (p.Arg30323Thr) 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:
RCV000184963.5

Allele description [Variation Report for NM_001267550.2(TTN):c.90968G>C (p.Arg30323Thr)]

NM_001267550.2(TTN):c.90968G>C (p.Arg30323Thr)

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.90968G>C (p.Arg30323Thr)
Other names:
p.R28682T:AGG>ACG
HGVS:
  • NC_000002.12:g.178551932C>G
  • NG_011618.3:g.283871G>C
  • NG_051363.1:g.34106C>G
  • NM_001256850.1:c.86045G>C
  • NM_001267550.2:c.90968G>CMANE SELECT
  • NM_003319.4:c.63773G>C
  • NM_133378.4:c.83264G>C
  • NM_133432.3:c.64148G>C
  • NM_133437.4:c.64349G>C
  • NP_001243779.1:p.Arg28682Thr
  • NP_001254479.2:p.Arg30323Thr
  • NP_003310.4:p.Arg21258Thr
  • NP_596869.4:p.Arg27755Thr
  • NP_597676.3:p.Arg21383Thr
  • NP_597681.4:p.Arg21450Thr
  • LRG_391:g.283871G>C
  • NC_000002.11:g.179416659C>G
Protein change:
R21258T
Links:
dbSNP: rs11887722
NCBI 1000 Genomes Browser:
rs11887722
Molecular consequence:
  • NM_001256850.1:c.86045G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001267550.2:c.90968G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003319.4:c.63773G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133378.4:c.83264G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133432.3:c.64148G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133437.4:c.64349G>C - 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
SCV000237738GeneDxcriteria provided, single submitter
Uncertain significance
(Sep 30, 2016)
germlineclinical testing

Citation Link,

SCV001623268Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(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, SCV000237738.6

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

Description

Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM panel(s).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623268.1

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

Description

Variant summary: TTN c.83264G>C (p.Arg27755Thr) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 248734 control chromosomes, predominantly at a frequency of 0.00081 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.83264G>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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

Last Updated: Jun 14, 2021

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