NM_001267550.2(TTN):c.3445G>A (p.Asp1149Asn) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Feb 27, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000152516.4

Allele description [Variation Report for NM_001267550.2(TTN):c.3445G>A (p.Asp1149Asn)]

NM_001267550.2(TTN):c.3445G>A (p.Asp1149Asn)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.3445G>A (p.Asp1149Asn)
HGVS:
  • NC_000002.12:g.178781199C>T
  • NG_011618.3:g.54604G>A
  • NM_001256850.1:c.3445G>A
  • NM_001267550.2:c.3445G>AMANE SELECT
  • NM_003319.4:c.3307G>A
  • NM_133378.4:c.3445G>A
  • NM_133379.5:c.3445G>A
  • NM_133432.3:c.3307G>A
  • NM_133437.4:c.3307G>A
  • NP_001243779.1:p.Asp1149Asn
  • NP_001254479.2:p.Asp1149Asn
  • NP_003310.4:p.Asp1103Asn
  • NP_596869.4:p.Asp1149Asn
  • NP_596870.2:p.Asp1149Asn
  • NP_597676.3:p.Asp1103Asn
  • NP_597681.4:p.Asp1103Asn
  • LRG_391:g.54604G>A
  • NC_000002.11:g.179645926C>T
Protein change:
D1103N
Links:
dbSNP: rs368967197
NCBI 1000 Genomes Browser:
rs368967197
Molecular consequence:
  • NM_001256850.1:c.3445G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001267550.2:c.3445G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003319.4:c.3307G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133378.4:c.3445G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133379.5:c.3445G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133432.3:c.3307G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133437.4:c.3307G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV000201696Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Uncertain significance
(Feb 27, 2019)
germlineclinical testing

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

SCV000725476GeneDxcriteria provided, single submitter
Likely benign
(Nov 30, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown21not 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 Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000201696.6

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

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Asp1149Asn variant in TTN has been identified in 1 individual with DCM who also had an additional splice site variant in TTN (LMM data). It has been identified in 0.016% (4/24970) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not provided1not provided

From GeneDx, SCV000725476.1

#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

Last Updated: Jul 7, 2021

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