rs375676529

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001267550.2(TTN):c.67604G>A(p.Ser22535Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,613,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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. S22535S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 0.445

Publications

2 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:

ENSG00000270574 (HGNC:):

ENSG00000270574 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.100043535).

BP6

Variant 2-178579593-C-T is Benign according to our data. Variant chr2-178579593-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220680.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.67604G>A	p.Ser22535Asn	missense_variant	Exon 319 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.67604G>A	p.Ser22535Asn	missense_variant	Exon 319 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000686

AC:

AN:

247796

AF XY:

0.0000967

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000120

AC:

175

AN:

1461146

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

726850

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33436

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000147

AC:

163

AN:

1111524

Other (OTH)

AF:

0.000149

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000125

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.0000414

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Feb 15, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31983221) -

Sep 01, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTN: PM2, BP4 -

Jun 02, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Mar 17, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TTN c.59900G>A (p.Ser19967Asn) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 247796 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (6.9e-05 vs 0.00039), allowing no conclusion about variant significance. c.59900G>A has been reported in the literature in at least one individual affected with Dilated Cardiomyopathy (Mazzarotto_2020). This report does not provide unequivocal conclusions about association of the variant with TTN-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 220680). Based on the evidence outlined above, the variant was classified as uncertain significance. -

TTN-related disorder

Uncertain:1

Jun 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TTN c.67604G>A variant is predicted to result in the amino acid substitution p.Ser22535Asn. This variant was reported in a large cohort study of individuals with dilated cardiomyopathy (Reported as chr2:g.179444320 in Supp. Table 3 Mazzarotto et al 2020. PubMed ID: 31983221). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. 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

Oct 20, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine with asparagine at codon 22535 of the TTN protein (c.67604G>A). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs375676529, ExAC 0.02%) but has not been reported in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiomyopathy

Uncertain:1

May 12, 2020

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 07, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico models in agreement (benign);Subpopulation frequency in support of benign classification -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.79

Eigen

Benign

0.12

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.70

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

M_CAP

Benign

0.031

MetaRNN

Benign

0.10

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

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.0

.;.;.;M;.;.;M

PhyloP100

0.45

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.8

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

REVEL

Benign

0.29

Sift

Benign

0.27

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

Polyphen

0.35

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

Vest4

0.21

MVP

0.24

MPC

0.14

ClinPred

0.094

GERP RS

4.9

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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rs375676529

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