rs184713215

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001267550.2(TTN):c.40973A>G(p.Lys13658Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000145 in 1,609,074 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. K13658K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:4

Conservation

PhyloP100: 3.86

Publications

7 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 links:

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]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06652439).

BP6

Variant 2-178636754-T-C is Benign according to our data. Variant chr2-178636754-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178220.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000144 (210/1456888) while in subpopulation MID AF = 0.00262 (15/5732). AF 95% confidence interval is 0.00161. There are 1 homozygotes in GnomAdExome4. There are 128 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.40973A>G	p.Lys13658Arg	missense_variant	Exon 225 of 363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.40973A>G	p.Lys13658Arg	missense_variant	Exon 225 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000162

AC:

AN:

246562

AF XY:

0.000202

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.0000880

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000223

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000144

AC:

210

AN:

1456888

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

128

AN XY:

724118

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33214

American (AMR)

AF:

0.000180

AC:

AN:

44394

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25996

East Asian (EAS)

AF:

0.00

AC:

AN:

39500

South Asian (SAS)

AF:

0.000372

AC:

AN:

85922

European-Finnish (FIN)

AF:

0.0000750

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00262

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.000119

AC:

132

AN:

1108708

Other (OTH)

AF:

0.000299

AC:

AN:

60122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000158

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41574

American (AMR)

AF:

0.000196

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000174

Hom.:

Bravo

AF:

0.000193

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000244

AC:

ExAC

AF:

0.000149

AC:

EpiCase

AF:

0.000328

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Jul 30, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TTN c.33269A>G (p.Lys11090Arg) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 1602136 control chromosomes in the gnomAD database (v4.1 dataset). In addition, within the South Asian subpopulation (allele frequency: 0.00037) the variant was fond in 1 homozygote. Furthermore, in certain ethnicities, e.g. in the Middle Eastern, the variant was reported with an even higher frequency (i.e. 0.0025), and which is about 6-times higher than the estimated maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), suggesting that the variant might be benign. The variant, c.33269A>G, has been reported in the literature in one individual affected with hypertrophic cardiomyopathy (Lopes_2013). These report(s) do 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. The following publication have been ascertained in the context of this evaluation (PMID: 23396983). ClinVar contains an entry for this variant (Variation ID: 178220). Based on the evidence outlined above, the variant was classified as likely benign. -

Jul 17, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Lys11090Arg variant in TTN has not been reported in individuals with cardiom yopathy, but has been identified in 2/8212 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs18471 321). Computational analyses (biochemical amino acid properties, conservation, A lignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an i mpact to the protein. Additional information is needed to fully assess the clini cal significance of this variant. -

not provided

Uncertain:1Benign:1

Dec 16, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 06, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23396983) -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G

Uncertain:1

Dec 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiomyopathy

Uncertain:1

Jul 08, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Uncertain:1

Mar 18, 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. -

Myopathy, myofibrillar, 9, with early respiratory failure

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Tibial muscular dystrophy

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.027

.;.;.;.;.;.;.;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.85

D;D;D;.;D;D;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.053

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.76

.;.;.;N;.;.;N;.

PhyloP100

3.9

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.6

N;N;.;.;N;N;.;N

REVEL

Benign

0.073

Sift

Benign

0.35

T;T;.;.;T;T;.;D

Polyphen

0.0020

.;.;.;B;.;.;B;.

Vest4

0.29

MVP

0.37

MPC

0.069

ClinPred

0.018

GERP RS

4.3

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over