rs397517497

Positions:

chr2-178790707-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_ModeratePP3_StrongPP5

The NM_001267550.2(TTN):c.1800+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000211 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

TTN
NM_001267550.2 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 5.11

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.0012688005 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-178790707-C-T is Pathogenic according to our data. Variant chr2-178790707-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46689.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}. Variant chr2-178790707-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.1800+1G>A		splice_donor_variant		ENST00000589042.5
TTN	NM_133379.5 linkuse as main transcript	c.1800+1G>A		splice_donor_variant		ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000360870.10 linkuse as main transcript	c.1800+1G>A		splice_donor_variant		5	NM_133379.5		Q8WZ42-6
TTN	ENST00000589042.5 linkuse as main transcript	c.1800+1G>A		splice_donor_variant		5	NM_001267550.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251382

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000490

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000705

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Muscular dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jun 18, 2017

- -

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 17, 2012

The 1800+1G>A variant in TTN has not been reported in the literature but has bee n identified in a child with DCM previously tested by our laboratory (LMM unpubl ished data). This variant has not been identified by large and broad European Am erican and African American populations screened by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS), which is consistent with a pathogenic role. However, we cannot exclude that it may be common in other populations. Th is variant occurs in the invariant region (+/- 1, 2) of the splice consensus seq uence and is predicted to cause altered splicing leading to an abnormal or absen t protein. Heterozygous loss of function of the TTN gene is strongly associated with DCM (Herman 2012). In summary, this variant is likely pathogenic, though ad ditional studies are required to fully establish its clinical significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 30, 2023

This sequence change affects a donor splice site in intron 11 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is present in population databases (rs397517497, gnomAD 0.05%). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy and/or distal myopathy (PMID: 34553419, 34935411). ClinVar contains an entry for this variant (Variation ID: 46689). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the Z band of TTN (PMID: 25589632). Non-truncating variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2022

Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Reported in an abstract, as a heterozygous variant in a child with high serum creatine kinase, mild motor weakness, mild sural hypertrophy, and muscle biopsy indicating a dystrophic process with reduced alpha-dystrophin staining, who also had a homozygous variant in the ISPD gene (Aksoy et al., 2019) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

GERP RS

5.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.59

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.59

Position offset: 1

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