NM_001267550.2(TTN):c.46387G>A (p.Gly15463Arg) AND not specified

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Apr 9, 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:: RCV000040270.13

Allele description [Variation Report for NM_001267550.2(TTN):c.46387G>A (p.Gly15463Arg)]

NM_001267550.2(TTN):c.46387G>A (p.Gly15463Arg)

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.46387G>A (p.Gly15463Arg)

Other names:

p.G13822R:GGG>AGG

HGVS:

NC_000002.12:g.178620030C>T
NG_011618.3:g.215773G>A
NG_051363.1:g.102204C>T
NM_001256850.1:c.41464G>A
NM_001267550.2:c.46387G>AMANE SELECT
NM_003319.4:c.19192G>A
NM_133378.4:c.38683G>A
NM_133432.3:c.19567G>A
NM_133437.4:c.19768G>A
NP_001243779.1:p.Gly13822Arg
NP_001254479.2:p.Gly15463Arg
NP_003310.4:p.Gly6398Arg
NP_596869.4:p.Gly12895Arg
NP_597676.3:p.Gly6523Arg
NP_597681.4:p.Gly6590Arg
LRG_391t1:c.46387G>A
LRG_391:g.215773G>A
NC_000002.11:g.179484757C>T
NM_001267550.1:c.46387G>A
NM_003319.4:c.19192G>A
NR_038271.1:n.1882C>T
c.38683G>A

Protein change:

G12895R

Links:

dbSNP: rs200042932

Molecular consequence:

NM_001256850.1:c.41464G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.46387G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.19192G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.38683G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.19567G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.19768G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_038271.1:n.1882C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000063961	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Mar 27, 2013)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21810661, 24033266
SCV005884998	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Dec 20, 2024)	germline	clinical testing	Citation Link,
SCV006068164	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 9, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000063961

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Mar 27, 2013)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005884998

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Dec 20, 2024)

germline

clinical testing

Citation Link,

SCV006068164

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Apr 9, 2025)

germline

clinical testing

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

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	2	2	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes.

Taylor M, Graw S, Sinagra G, Barnes C, Slavov D, Brun F, Pinamonti B, Salcedo EE, Sauer W, Pyxaras S, Anderson B, Simon B, Bogomolovas J, Labeit S, Granzier H, Mestroni L.

Circulation. 2011 Aug 23;124(8):876-85. doi: 10.1161/CIRCULATIONAHA.110.005405. Epub 2011 Aug 1.

PubMed [citation]

PMID:: 21810661
PMCID:: PMC3167235

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

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000063961.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (2)

Description

The Gly12895Arg variant in TTN has not been reported in the literature, but has been identified by our laboratory in one individual with DCM (LMM unpublished da ta). This variant has been identified in 3/8228 European American chromosomes f rom a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS/; dbSNP rs200042932). Computational analyses (biochemical amino a cid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the G ly12895Arg variant may impact the protein, though this information is not predic tive enough to determine pathogenicity. In summary, additional information is ne eded to fully assess the clinical significance of the Gly12895Arg variant.

#	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		2	not provided	2	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005884998.1

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

Description

Variant summary: TTN c.38683G>A (p.Gly12895Arg) results in a non-conservative amino acid change located in the I-band domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 246698 control chromosomes, predominantly at a frequency of 0.00051 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 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039). To our knowledge, no occurrence of c.38683G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 47000). 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

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV006068164.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 11, 2026

ClinVar

Relating variation to medicine