NM_001267550.2(TTN):c.12145C>T (p.Pro4049Ser) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(3) (Last evaluated: Jan 1, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000172704.7

Allele description [Variation Report for NM_001267550.2(TTN):c.12145C>T (p.Pro4049Ser)]

NM_001267550.2(TTN):c.12145C>T (p.Pro4049Ser)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.12145C>T (p.Pro4049Ser)
HGVS:
  • NC_000002.12:g.178741088G>A
  • NG_011618.3:g.94715C>T
  • NM_001256850.1:c.11194C>T
  • NM_001267550.2:c.12145C>TMANE SELECT
  • NM_003319.4:c.11056C>T
  • NM_133378.4:c.10361-2728C>T
  • NM_133432.3:c.11431C>T
  • NM_133437.4:c.11632C>T
  • NP_001243779.1:p.Pro3732Ser
  • NP_001254479.2:p.Pro4049Ser
  • NP_003310.4:p.Pro3686Ser
  • NP_597676.3:p.Pro3811Ser
  • NP_597681.4:p.Pro3878Ser
  • LRG_391t1:c.12145C>T
  • LRG_391:g.94715C>T
  • NC_000002.11:g.179605815G>A
  • NM_001267550.1:c.12145C>T
  • c.11431C>T
Protein change:
P3686S
Links:
dbSNP: rs201888760
NCBI 1000 Genomes Browser:
rs201888760
Molecular consequence:
  • NM_133378.4:c.10361-2728C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001256850.1:c.11194C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001267550.2:c.12145C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003319.4:c.11056C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133432.3:c.11431C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133437.4:c.11632C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
6

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000051258Biesecker Lab/Clinical Genomics Section,National Institutes of Health - ClinSeqcriteria provided, single submitter
Likely benign
(Jun 24, 2013)
unknownresearch

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

SCV000701607EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Uncertain significance
(May 16, 2017)
germlineclinical testing

Citation Link,

SCV000844618Athena Diagnostics Inccriteria provided, single submitter
Uncertain significance
(Feb 20, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001153104CeGaT Praxis fuer Humangenetik Tuebingencriteria provided, single submitter
Uncertain significance
(Jan 1, 2020)
germlineclinical testing

Citation Link,

SCV001552712Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedUncertain significanceunknownclinical testing

SCV001743362Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensusno assertion criteria providedUncertain significancegermlineclinical testing

Description

The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details.

SCV000051258

Medical sequencing

SCV000051258

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknown2not providednot providednot providednot providedresearch
not providedgermlineyes3not providednot providednot providednot providedclinical testing
not providedgermlineunknown3not providednot providednot providednot providedclinical testing

Citations

PubMed

Titin Truncating Variants in Dilated Cardiomyopathy - Prevalence and Genotype-Phenotype Correlations.

Franaszczyk M, Chmielewski P, Truszkowska G, Stawinski P, Michalak E, Rydzanicz M, Sobieszczanska-Malek M, Pollak A, Szczygieł J, Kosinska J, Parulski A, Stoklosa T, Tarnowska A, Machnicki MM, Foss-Nieradko B, Szperl M, Sioma A, Kusmierczyk M, Grzybowski J, Zielinski T, Ploski R, Bilinska ZT.

PLoS One. 2017;12(1):e0169007. doi: 10.1371/journal.pone.0169007.

PubMed [citation]
PMID:
28045975
PMCID:
PMC5207678

Interpreting secondary cardiac disease variants in an exome cohort.

Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG; NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program..

Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.

PubMed [citation]
PMID:
23861362
PMCID:
PMC3887521
See all PubMed Citations (3)

Details of each submission

From Biesecker Lab/Clinical Genomics Section,National Institutes of Health - ClinSeq, SCV000051258.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot provided2not providednot providednot provided

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000701607.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided3not providednot providednot provided

From Athena Diagnostics Inc, SCV000844618.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From CeGaT Praxis fuer Humangenetik Tuebingen, SCV001153104.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided3not providednot providednot provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001552712.1

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

Description

The TTN p.Pro3878Ser variant was identified in 1 of 144 proband chromosomes (frequency: 0.0069) from an individual with dilated cardiomyopathy who also carried a TTN truncating mutation (Franaszczyk_2017_PMID:28045975). The variant was identified in dbSNP (ID: rs201888760) and ClinVar (classified as likely benign by Biesecker Lab and GeneDx and uncertain significance by Invitae, Athena Diagnostics Inc, Laboratory for Molecular Medicine and EGL Genetic Diagnostics). The variant was identified in control databases in 104 of 279690 chromosomes (1 homozygous) at a frequency of 0.0003718 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 11 of 10328 chromosomes (freq: 0.001065), Other in 7 of 7110 chromosomes (freq: 0.000985), European (non-Finnish) in 63 of 127606 chromosomes (freq: 0.000494), South Asian in 13 of 30594 chromosomes (freq: 0.000425), Latino in 6 of 35360 chromosomes (freq: 0.00017) and African in 4 of 24182 chromosomes (freq: 0.000165), but was not observed in the East Asian, or European (Finnish) populations. The p.Pro3878 residue has limited species conservation data and computational analyses (BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001743362.3

#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 7, 2021

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