NM_001267550.2(TTN):c.53012C>T (p.Ala17671Val) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Nov 6, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000152326.2

Allele description [Variation Report for NM_001267550.2(TTN):c.53012C>T (p.Ala17671Val)]

NM_001267550.2(TTN):c.53012C>T (p.Ala17671Val)

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.53012C>T (p.Ala17671Val)
HGVS:
  • NC_000002.12:g.178607676G>A
  • NG_011618.3:g.228127C>T
  • NG_051363.1:g.89850G>A
  • NM_001256850.1:c.48089C>T
  • NM_001267550.2:c.53012C>TMANE SELECT
  • NM_003319.4:c.25817C>T
  • NM_133378.4:c.45308C>T
  • NM_133432.3:c.26192C>T
  • NM_133437.4:c.26393C>T
  • NP_001243779.1:p.Ala16030Val
  • NP_001254479.2:p.Ala17671Val
  • NP_003310.4:p.Ala8606Val
  • NP_596869.4:p.Ala15103Val
  • NP_597676.3:p.Ala8731Val
  • NP_597681.4:p.Ala8798Val
  • LRG_391:g.228127C>T
  • NC_000002.11:g.179472403G>A
Protein change:
A15103V
Links:
dbSNP: rs549478203
NCBI 1000 Genomes Browser:
rs549478203
Molecular consequence:
  • NM_001256850.1:c.48089C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001267550.2:c.53012C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003319.4:c.25817C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133378.4:c.45308C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133432.3:c.26192C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133437.4:c.26393C>T - 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
SCV000201215Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Uncertain significance
(Nov 6, 2017)
germlineclinical testing

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

SCV000719582GeneDxcriteria provided, single submitter
Likely benign
(May 16, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided21not 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, SCV000201215.5

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

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Ala15103Val v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 5/23972 of African chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs549478203). A lanine (Ala) at position 15103 is not conserved in mammals or evolutionarily dis tant species and at least 10 fish species carry a valine (Val) at this position, raising the possibility that a change at this position may be tolerated. Additi onal computational prediction tools suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogeni city. In summary, while the clinical significance of the p.Ala15103Val variant i s uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Cr iteria applied: BP4 (Richards 2015).

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

From GeneDx, SCV000719582.1

#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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