NM_001267550.2(TTN):c.44077C>T (p.Arg14693Cys) AND not specified

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Jun 10, 2025
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:: RCV000219227.13

Allele description [Variation Report for NM_001267550.2(TTN):c.44077C>T (p.Arg14693Cys)]

NM_001267550.2(TTN):c.44077C>T (p.Arg14693Cys)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.44077C>T (p.Arg14693Cys)

Other names:

p.R12125C:CGC>TGC

HGVS:

NC_000002.12:g.178630881G>A
NG_011618.3:g.204922C>T
NM_001256850.1:c.39154C>T
NM_001267550.2:c.44077C>TMANE SELECT
NM_003319.4:c.16882C>T
NM_133378.4:c.36373C>T
NM_133432.3:c.17257C>T
NM_133437.4:c.17458C>T
NP_001243779.1:p.Arg13052Cys
NP_001254479.2:p.Arg14693Cys
NP_003310.4:p.Arg5628Cys
NP_596869.4:p.Arg12125Cys
NP_597676.3:p.Arg5753Cys
NP_597681.4:p.Arg5820Cys
LRG_391:g.204922C>T
NC_000002.11:g.179495608G>A

Protein change:

R12125C

Links:

dbSNP: rs200445568

Molecular consequence:

NM_001256850.1:c.39154C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.44077C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.16882C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.36373C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.17257C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.17458C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000272647	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 28, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001448485	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jun 10, 2025)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26771497, 27149842, 30086531, 27302369, 34598035 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000272647

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 28, 2015)

germline

clinical testing

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

SCV001448485

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jun 10, 2025)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance.

Marcotte R, Sayad A, Brown KR, Sanchez-Garcia F, Reimand J, Haider M, Virtanen C, Bradner JE, Bader GD, Mills GB, Pe'er D, Moffat J, Neel BG.

Cell. 2016 Jan 14;164(1-2):293-309. doi: 10.1016/j.cell.2015.11.062.

PubMed [citation]

PMID:: 26771497
PMCID:: PMC4724865

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000272647.3

#	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 p.Arg12125Cys v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 0.2% (20/9970) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200445568 ). Computational prediction tools and conservation analysis suggest that this va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity. In summary, while the clinical significance of the p. Arg12125Cys variant is uncertain, its frequency suggests 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, SCV001448485.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: TTN c.36373C>T (p.Arg12125Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00017 in 248510 control chromosomes, predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5.63 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039). c.36373C>T has been reported in the literature in one individual affected with sudden cardiac death (Campuzano_2018). These report(s) do not provide unequivocal conclusions about association of the variant with TTN-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30086531, 34598035, 27302369, 27149842, 26771497). ClinVar contains an entry for this variant (Variation ID: 194910). 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: Jul 28, 2025

ClinVar

Relating variation to medicine