NM_001267550.2(TTN):c.55374C>G (p.Ser18458Arg) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Aug 30, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000152301.7

Allele description [Variation Report for NM_001267550.2(TTN):c.55374C>G (p.Ser18458Arg)]

NM_001267550.2(TTN):c.55374C>G (p.Ser18458Arg)

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.55374C>G (p.Ser18458Arg)
Other names:
p.S16817R:AGC>AGG
HGVS:
  • NC_000002.12:g.178601716G>C
  • NG_011618.3:g.234087C>G
  • NG_051363.1:g.83890G>C
  • NM_001256850.1:c.50451C>G
  • NM_001267550.2:c.55374C>GMANE SELECT
  • NM_003319.4:c.28179C>G
  • NM_133378.4:c.47670C>G
  • NM_133432.3:c.28554C>G
  • NM_133437.4:c.28755C>G
  • NP_001243779.1:p.Ser16817Arg
  • NP_001254479.2:p.Ser18458Arg
  • NP_003310.4:p.Ser9393Arg
  • NP_596869.4:p.Ser15890Arg
  • NP_597676.3:p.Ser9518Arg
  • NP_597681.4:p.Ser9585Arg
  • LRG_391:g.234087C>G
  • NC_000002.11:g.179466443G>C
Protein change:
S15890R
Links:
dbSNP: rs200550947
NCBI 1000 Genomes Browser:
rs200550947
Molecular consequence:
  • NM_001256850.1:c.50451C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001267550.2:c.55374C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003319.4:c.28179C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133378.4:c.47670C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133432.3:c.28554C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133437.4:c.28755C>G - 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
SCV000201168Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Uncertain significance
(Aug 27, 2014)
germlineclinical testing

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

SCV001821441Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Aug 30, 2021)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot 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

A novel TTN deletion in a family with skeletal myopathy, facial weakness, and dilated cardiomyopathy.

Roggenbuck J, Rich K, Morales A, Tan CA, Eck D, King W, Vatta M, Winder T, Elsheikh B, Hershberger RE, Kissel JT.

Mol Genet Genomic Med. 2019 Nov;7(11):e924. doi: 10.1002/mgg3.924. Epub 2019 Sep 5.

PubMed [citation]
PMID:
31489791
PMCID:
PMC6825852

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000201168.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

Variant classified as Uncertain Significance - Favor Benign. The Ser15890Arg var iant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (10/8194) of European American chromosomes by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs20 0550947). Computational prediction tools and conservation analysis do not provid e strong support for or against an impact to the protein. In summary, while the clinical significance of the Ser15890Arg variant is uncertain, its frequency sug gests that it is more likely to be benign.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001821441.1

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

Description

Variant summary: TTN c.47670C>G (p.Ser15890Arg) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 277010 control chromosomes, predominantly at a frequency of 0.0007 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European 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 Non-Finnish European origin. c.47670C>G has been reported in the literature in one individual affected with Dilated Cardiomyopathy (Roggenbuck_2019). The report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Additionally, one co-occurrence with another pathogenic variant has been reported (exons 346-362 deletion; Roggenbuck_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=1). 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: Oct 6, 2021

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