rs377506142

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001267550.2(TTN):​c.80858C>T​(p.Thr26953Met) variant causes a missense change. The variant allele was found at a frequency of 0.000401 in 1,613,564 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T26953T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00042 ( 5 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

1
5
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:11

Conservation

PhyloP100: 6.84
Variant links:
Genes affected
TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]
TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010902077).
BP6
Variant 2-178565274-G-A is Benign according to our data. Variant chr2-178565274-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179002.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2, Benign=6}. Variant chr2-178565274-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000243 (37/152152) while in subpopulation SAS AF = 0.00705 (34/4824). AF 95% confidence interval is 0.00518. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
BS2
High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.80858C>T p.Thr26953Met missense_variant Exon 326 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.80858C>T p.Thr26953Met missense_variant Exon 326 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
152034
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00704
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000919
AC:
228
AN:
248210
AF XY:
0.00124
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000268
Gnomad OTH exome
AF:
0.000995
GnomAD4 exome
AF:
0.000417
AC:
610
AN:
1461412
Hom.:
5
Cov.:
37
AF XY:
0.000605
AC XY:
440
AN XY:
727016
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
AC:
2
AN:
33460
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
44716
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26122
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39672
Gnomad4 SAS exome
AF:
0.00654
AC:
564
AN:
86248
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53388
Gnomad4 NFE exome
AF:
0.0000117
AC:
13
AN:
1111684
Gnomad4 Remaining exome
AF:
0.000514
AC:
31
AN:
60358
Heterozygous variant carriers
0
39
78
118
157
196
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000243
AC:
37
AN:
152152
Hom.:
0
Cov.:
33
AF XY:
0.000350
AC XY:
26
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.0000241
AC:
0.000024072
AN:
0.000024072
Gnomad4 AMR
AF:
0.00
AC:
0
AN:
0
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.000194
AC:
0.000193723
AN:
0.000193723
Gnomad4 SAS
AF:
0.00705
AC:
0.00704809
AN:
0.00704809
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.0000147
AC:
0.0000147085
AN:
0.0000147085
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000333
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.000977
AC:
118
Asia WGS
AF:
0.00433
AC:
15
AN:
3478
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:11
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:4
Feb 18, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

TTN: BP4 -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

not specified Uncertain:1Benign:2
Aug 27, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The Thr24385Met variant in TTN has previously been identified by our laboratory in 1 adult with HCM, and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, though 1 mammal (pika) carries a methionine ( Met; this variant) at this position, raising the possibility that this change ma y be tolerated. In summary, the clinical significance of the Thr24385Met variant is uncertain. -

Feb 25, 2020
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Dilated cardiomyopathy 1G Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Early-onset myopathy with fatal cardiomyopathy Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiovascular phenotype Uncertain:1
Nov 20, 2013
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.T24385M variant (also known as c.73154C>T) is located in coding exon 274 of the TTN gene. This alteration results from a C to T substitution at nucleotide position 73154. The threonine at codon 24385 is replaced by methionine, an amino acid with some similar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), the 1000 Genomes Project and the NHLBI Exome Sequencing Project (ESP). In the ESP, this variant was not reported in 6002 samples (12004 alleles) with coverage at this position. Based on protein sequence alignment, this amino acid position is well conserved in available vertebrate species, though methionine is the reference amino acid in one species.In addition, this alteration is predicted to be benign by PolyPhen analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiomyopathy Benign:1
Feb 20, 2018
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Tibial muscular dystrophy Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Primary dilated cardiomyopathy Benign:1
-
Genetics and Genomics Program, Sidra Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
20
DANN
Benign
0.80
Eigen
Benign
0.18
Eigen_PC
Benign
0.22
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
D;D;D;.;D;D;D
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.011
T;T;T;T;T;T;T
MetaSVM
Benign
-0.52
T
MutationAssessor
Uncertain
2.4
.;.;.;M;.;.;M
PrimateAI
Benign
0.38
T
PROVEAN
Uncertain
-4.0
D;D;.;.;D;D;.
REVEL
Uncertain
0.30
Sift
Uncertain
0.0040
D;D;.;.;D;D;.
Polyphen
0.51
.;.;.;P;.;.;P
Vest4
0.21
MutPred
0.57
.;.;.;Loss of glycosylation at T25312 (P = 0.0438);.;.;Loss of glycosylation at T25312 (P = 0.0438);
MVP
0.59
MPC
0.12
ClinPred
0.13
T
GERP RS
4.8
Mutation Taster
=99/1
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs377506142; hg19: chr2-179430001; COSMIC: COSV59900531; API