chr2-178591977-C-T

Position:

chr2-178591977-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001267550.2(TTN):c.59926+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000343 in 1,459,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TTN
NM_001267550.2 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 6.04

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:):

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0027691338 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-178591977-C-T is Pathogenic according to our data. Variant chr2-178591977-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 574210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178591977-C-T is described in Lovd as [Pathogenic]. Variant chr2-178591977-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.59926+1G>A		splice_donor_variant, intron_variant		ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.59926+1G>A		splice_donor_variant, intron_variant		5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245926

Hom.:

AF XY:

0.00000750

AC XY:

AN XY:

133414

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459092

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725704

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	TTN: PVS1:Strong, PM1, PM2, PS4:Moderate -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2025	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Located in the A-band, a region of TTN for which truncating variants are significantly associated with autosomal dominant cardiomyopathy and also with autosomal recessive skeletal myopathies (PMID: 22335739, 32778822); This variant is associated with the following publications: (PMID: 29650543, 37183561, 30847666, 36344503, 31112426, 32964742, 31737537, 22335739, 34011823, 33662488, 32778822, 32880476, 29057560) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

TTN-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2024

The TTN c.59926+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in numerous individuals with dilated cardiomyopathy (described as c.55003+1G>A in Table S4, Herman et al. 2012. PubMed ID: 22335739; described as c.52222+1G>A in online supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666; Marschall et al. 2019. PubMed ID: 31737537; Table S2, Akhtar et al. 2020. PubMed ID: 32964742; Alimohamed et al. 2021. PubMed ID: 33662488). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant disrupts the splice donor site of an exon which is located in the A-band region of the protein and is predicted to result in an in-frame deletion of 100 amino acids. RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 91%-100%); however, this analysis in muscle tissue was not performed (Roberts et al. 2015. PMID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in the heterozygous state in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating this variant is more likely to be disease causing (Herman et al. 2012. PMID: 22335739; Roberts et al. 2015. PMID: 25589632). In summary, this variant is interpreted as pathogenic for both autosomal dominant and autosomal recessive TTN-related disorders. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 2023

This sequence change affects a donor splice site in intron 302 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 (rs553526525, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 22335739, 29057560). It has also been observed to segregate with disease in related individuals. This variant is also known as c.55003+1G>A. ClinVar contains an entry for this variant (Variation ID: 574210). 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 A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1G

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

KTest Genetics, KTest

- -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 01, 2022

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.32731+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 129 of the TTN gene. Exon 129 is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). One study reported this variant (referred to as NM_001267550:c.59926+1G>A) as a potential Netherlands founder mutation, having been detected in 11 probands with dilated cardiomyopathy (DCM) and showing strong segregation with disease in families (Hoorntje ET et al. Eur J Heart Fail, 2018 Apr;20:803-806). This variant (also referred to as NM_001256850:c.55003+1G>A) has also been detected in additional unrelated probands from other DCM cohorts (Herman DS et al. N Engl J Med, 2012 Feb;366:619-28; Nguyen TV et al. Circ J, 2021 Aug;85:1469-1478). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown. This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Uncertain

0.94

GERP RS

6.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

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