NM_001267550.2(TTN):c.41166C>T (p.Asp13722=) AND not specified

Clinical significance:Benign/Likely benign (Last evaluated: Oct 30, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000154954.6

Allele description [Variation Report for NM_001267550.2(TTN):c.41166C>T (p.Asp13722=)]

NM_001267550.2(TTN):c.41166C>T (p.Asp13722=)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.41166C>T (p.Asp13722=)
HGVS:
  • NC_000002.12:g.178636561G>A
  • NG_011618.3:g.199242C>T
  • NM_001256850.1:c.36243C>T
  • NM_001267550.2:c.41166C>TMANE SELECT
  • NM_003319.4:c.13971C>T
  • NM_133378.4:c.33462C>T
  • NM_133432.3:c.14346C>T
  • NM_133437.4:c.14547C>T
  • NP_001243779.1:p.Asp12081=
  • NP_001254479.2:p.Asp13722=
  • NP_003310.4:p.Asp4657=
  • NP_596869.4:p.Asp11154=
  • NP_597676.3:p.Asp4782=
  • NP_597681.4:p.Asp4849=
  • LRG_391:g.199242C>T
  • NC_000002.11:g.179501288G>A
  • NP_596869.4:p.(=)
  • p.Asp11154Asp
Links:
dbSNP: rs143049740
NCBI 1000 Genomes Browser:
rs143049740
Molecular consequence:
  • NM_001256850.1:c.36243C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001267550.2:c.41166C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_003319.4:c.13971C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_133378.4:c.33462C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_133432.3:c.14346C>T - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_133437.4:c.14547C>T - synonymous variant - [Sequence Ontology: SO:0001819]
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
SCV000203715EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Likely benign
(Aug 17, 2017)
germlineclinical testing

Citation Link,

SCV000204636Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely benign
(Jan 23, 2017)
germlineclinical testing

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

SCV000515130GeneDxcriteria provided, single submitter
Benign
(Aug 13, 2015)
germlineclinical testing

Citation Link,

SCV001361799Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Benign
(Oct 30, 2019)
germlineclinical testing

Citation Link,

SCV001917334Clinical Genetics,Academic Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria providedBenigngermlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided22not providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown4not 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 EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000203715.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided4not providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000204636.5

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

Description

p.Asp11154Asp in exon 174 of TTN: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence. It has been identified in 0.2% (22/9794) of A frican chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs143049740).

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

From GeneDx, SCV000515130.4

#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, SCV001361799.1

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

Description

Variant summary: TTN c.33462C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 248322 control chromosomes, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.36 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.33462C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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

From Clinical Genetics,Academic Medical Center - VKGL Data-share Consensus, SCV001917334.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 24, 2021

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