2-178557987-T-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267550.2(TTN):c.87367A>C(p.Ser29123Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,613,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 4.14

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:

ENSG00000279598 (HGNC:):

ENSG00000279598 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23306492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.87367A>C	p.Ser29123Arg	missense_variant	Exon 328 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.87367A>C	p.Ser29123Arg	missense_variant	Exon 328 of 363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000925

AC:

AN:

248516

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

134820

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000110

AC:

161

AN:

1461382

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

726994

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Dec 11, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30453078) -

Sep 21, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:2

Dec 11, 2024

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.79663A>C in NM_133378 (p.Ser26555Arg, exon 277) (also reported as c.87367A>C p.Ser29123Arg in Exon 328 NM_001267550), results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Nonsense, frameshift, and canonical splice-site variants in all TTN exon bands are strongly associated with a spectrum of autosomal recessive titinopathies (PMID: 32778822, 29691892, 33449170, 36977548, internal data). The clear majority (>90%) of recessive titinopathy cases require exon expression (proportion spliced in, PSI, 1=complete expression) in skeletal muscle to be PSI >0.1 (PMID: 36977548, 39198997, 29598826). In contrast, loss of function variants are only strongly associated with autosomal dominant TTN-related cardiomyopathies if located in exons constitutively expressed (PSI >0.9) in cardiac muscle, excluding extreme C-terminal exons 359-363 (PMID: 25589632, 31216868, 32964742, 34662387, 27869827, Shetty et al., Nat Cardiovasc Res 2024, cardiodb.org, internal data). This variant is located in the A-band region with a maximum skeletal muscle PSI of 0.94 in PMID 39198997 and maximum cardiac muscle PSI of 1 in cardiodb.org. The variant allele was found at a frequency of 9.3e-05 in 248516 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Autosomal Recessive Titinopathy (9.3e-05 vs 0.00039), allowing no conclusion about variant significance. c.79663A>C has been reported in the literature in one unspecified individual affected with Arrhythmogenic cardiomyopathy, in trans along with another VUS missense change (Poloni_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Titinopathy. 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: 30453078). ClinVar contains an entry for this variant (Variation ID: 47463). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Feb 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ser26555Arg variant (TTN) has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, and SIFT) do not provide strong support f or or against an impact to the protein. Additional information is needed to full y assess the clinical significance of the Ser26555Arg variant. -

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

Uncertain:1

Dec 08, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Uncertain:1

Apr 27, 2021

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

Uncertain:1

Sep 24, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S20058R variant (also known as c.60172A>C), located in coding exon 155 of the TTN gene, results from an A to C substitution at nucleotide position 60172. The serine at codon 20058 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.95

D;D;D;.;D;D;D

M_CAP

Benign

0.048

MetaRNN

Benign

0.23

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

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.6

.;.;.;L;.;.;L

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.1

D;D;.;.;D;D;.

REVEL

Benign

0.24

Sift

Uncertain

0.028

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

Polyphen

0.98

.;.;.;D;.;.;D

Vest4

0.55

MutPred

0.52

.;.;.;Loss of glycosylation at S27482 (P = 0.0079);.;.;Loss of glycosylation at S27482 (P = 0.0079);

MVP

0.32

MPC

0.13

ClinPred

0.043

GERP RS

5.6

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over