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

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 16, 2020
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:: RCV000219227.11

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

NCBI 1000 Genomes Browser:

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

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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 (Nov 16, 2020)	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

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
(Nov 16, 2020)

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	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	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

Molecular autopsy in a cohort of infants died suddenly at rest.

Campuzano O, Beltramo P, Fernandez A, Iglesias A, García L, Allegue C, Sarquella-Brugada G, Coll M, Perez-Serra A, Mademont-Soler I, Mates J, Del Olmo B, Rodríguez Á, Maciel N, Puigmulé M, Pico F, Cesar S, Brugada J, Cuesta A, Gutierrez C, Brugada R.

Forensic Sci Int Genet. 2018 Nov;37:54-63. doi: 10.1016/j.fsigen.2018.07.023. Epub 2018 Jul 31.

PubMed [citation]

PMID:: 30086531

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, SCV001448485.1

#	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.36373C>T (p.Arg12125Cys) results in a non-conservative amino acid change located in the I-band domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 279870 control chromosomes, predominantly at a frequency of 0.0024 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 6 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 African or African-American origin. c.36373C>T has been reported in the literature in one individual affected with sudden cardiac death (Campuzano_2018). The report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x) and likely benign (3x). 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: Oct 13, 2024

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