chr2-178529076-C-G

Variant summary

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

The NM_001267550.2(TTN):​c.106675G>C​(p.Glu35559Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,613,336 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00030 ( 0 hom., cov: 33)
Exomes š‘“: 0.00038 ( 3 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

2
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:12

Conservation

PhyloP100: 1.61

Publications

4 publications found
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=0.021069646).
BP6
Variant 2-178529076-C-G is Benign according to our data. Variant chr2-178529076-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 192135.
BS1
Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000379 (554/1461086) while in subpopulation MID AF = 0.00312 (18/5766). AF 95% confidence interval is 0.00202. There are 3 homozygotes in GnomAdExome4. There are 294 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.106675G>C p.Glu35559Gln missense_variant Exon 360 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.106675G>C p.Glu35559Gln missense_variant Exon 360 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.000296
AC:
45
AN:
152132
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000426
Gnomad OTH
AF:
0.000955
GnomAD2 exomes
AF:
0.000426
AC:
106
AN:
248704
AF XY:
0.000504
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.000796
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000140
Gnomad NFE exome
AF:
0.000470
Gnomad OTH exome
AF:
0.000830
GnomAD4 exome
AF:
0.000379
AC:
554
AN:
1461086
Hom.:
3
Cov.:
32
AF XY:
0.000405
AC XY:
294
AN XY:
726800
show subpopulations
African (AFR)
AF:
0.000120
AC:
4
AN:
33402
American (AMR)
AF:
0.0000448
AC:
2
AN:
44636
Ashkenazi Jewish (ASJ)
AF:
0.000727
AC:
19
AN:
26128
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.00115
AC:
99
AN:
86196
European-Finnish (FIN)
AF:
0.0000938
AC:
5
AN:
53304
Middle Eastern (MID)
AF:
0.00312
AC:
18
AN:
5766
European-Non Finnish (NFE)
AF:
0.000332
AC:
369
AN:
1111640
Other (OTH)
AF:
0.000630
AC:
38
AN:
60322
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.491
Heterozygous variant carriers
0
37
74
112
149
186
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<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:
0.000296
AC:
45
AN:
152250
Hom.:
0
Cov.:
33
AF XY:
0.000296
AC XY:
22
AN XY:
74412
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41556
American (AMR)
AF:
0.000131
AC:
2
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00187
AC:
9
AN:
4822
European-Finnish (FIN)
AF:
0.0000943
AC:
1
AN:
10604
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000426
AC:
29
AN:
68010
Other (OTH)
AF:
0.000945
AC:
2
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
3
5
8
10
13
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

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:
0.000409
Hom.:
0
Bravo
AF:
0.000249
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000275
AC:
1
ESP6500EA
AF:
0.000245
AC:
2
ExAC
AF:
0.000414
AC:
50
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000491
EpiControl
AF:
0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:12
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:5
Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:research

- -

Oct 04, 2023
Revvity Omics, Revvity
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 10, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27930701, 23861362, 28440294) -

Nov 05, 2019
Athena Diagnostics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 22, 2019
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

TTN: BP4 -

not specified Uncertain:1Benign:3
Apr 09, 2025
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 10, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Glu32991Gln v ariant has been identified by our laboratory in 1 Caucasian individual with idio pathic cardiomyopathy and in 0.1% (34/30728) of South Asian chromosomes by the G enome Aggreagation Database (gnomAD, http://gnomad.broadinstitute.org/, dbSNP rs 199632397). This variant was also identified in a 23-year-old female who died su ddenly; however, the specific cause of her death was unexplained even after auto psy (Sanchez 2016). This variant has also been reported in ClinVar (Variation ID 192135). Computational prediction tools and conservation analysis suggest that the p.Glu32991Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Glu32991Gln variant is uncertain, its frequency suggests that it is more likely to be benign. -

Sep 01, 2015
Eurofins Ntd Llc (ga)
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 22, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiovascular phenotype Uncertain:1Benign:1
Jul 04, 2019
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 14, 2013
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

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. -

TTN-related disorder Uncertain:1
Jul 06, 2023
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The TTN c.106675G>C variant is predicted to result in the amino acid substitution p.Glu35559Gln. This variant, along with two additional TTN variants, was reported in one case of sudden death, however no additional studies were performed to help assess the pathogenicity of this variant (described as c.98971G>C (p.Glu32991Gln) with an alternate transcript NM_133378, Sanchez et al. 2016. PubMed ID: 27930701). This variant is reported in 0.11% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179393803-C-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Nov 21, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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. -

TTN-related myopathy Uncertain:1
Mar 22, 2021
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The TTN c.106675G>C (p.Glu35559Gln) variant is a missense variant. The p.Glu35559Gln variant has been reported in one publication in which it is described as c.98971G>C (p.Glu32991Gln). The variant was identified in a heterozygous state in a 23 year-old female with sudden unexplained death. The p.Glu35559Gln variant has not been reported in association with autosomal dominant or recessive TTN-related myopathies. The p.Glu35559Gln variant is reported at a frequency of 0.001146 in the South Asian population of the Genome Aggregation Database. Although this frequency is too high to suggest an association with dominant TTN-related phenotypes, it is consistent with a potential association with autosomal recessive phenotypes. This variant is located within the M band of the protein. In silico prediction of pathogenicity for this variant are mixed, but lean towards benign. However, currently available in silico prediction tools may have limited utility in the assessment of missense variants in the TTN gene (Rees et al. 2021). Based on the limited evidence and application of the ACMG criteria, the p.Glu35559Gln variant is classified as a variant of uncertain significance for TTN-related myopathy. -

Cardiomyopathy Benign:1
Mar 24, 2023
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
17
DANN
Benign
0.85
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.83
T;T;T;.;T;T;T
M_CAP
Benign
0.041
D
MetaRNN
Benign
0.021
T;T;T;T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
0.55
.;.;.;N;.;.;N
PhyloP100
1.6
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-1.6
N;N;.;.;N;N;.
REVEL
Benign
0.098
Sift
Benign
0.065
.;T;.;.;T;T;.
Polyphen
0.60
.;.;.;P;.;.;P
Vest4
0.26
MVP
0.35
MPC
0.12
ClinPred
0.026
T
GERP RS
5.5
Mutation Taster
=93/7
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

Other links and lift over

dbSNP: rs199632397; hg19: chr2-179393803; API