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

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Aug 30, 2021
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000152301.14

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
NM_003319.4:c.28179C>G

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:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000201168	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Aug 27, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001821441	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Aug 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000201168

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Aug 27, 2014)

germline

clinical testing

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

SCV001821441

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Aug 30, 2021)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical 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, Mass General Brigham Personalized Medicine, SCV000201168.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 13, 2025

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