2-178675038-C-T

Variant names:

• chr2-178675038-C-T
• rs577363824
• NM_001267550.2:c.34612+1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The NM_001267550.2(TTN):​c.34612+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000158 in 1,523,594 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TTN NM_001267550.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.50
• Publications: 0 publications found

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-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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 6.945988E-4 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 2-178675038-C-T is Pathogenic according to our data. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922. Variant chr2-178675038-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 404922.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.34612+1G>A		splice_donor_variant, intron_variant	Intron 150 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.34612+1G>A		splice_donor_variant, intron_variant	Intron 150 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151844 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 3 AN: 185860 AF XY: 0.0000195

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000329

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000160 AC: 22 AN: 1371750 Hom.: 0 Cov.: 26 AF XY: 0.0000162 AC XY: 11 AN XY: 680558

African (AFR) AF: 0.00 AC: 0 AN: 28010

American (AMR) AF: 0.00 AC: 0 AN: 29788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24080

East Asian (EAS) AF: 0.00 AC: 0 AN: 33564

South Asian (SAS) AF: 0.0000143 AC: 1 AN: 69768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.0000196 AC: 21 AN: 1071830

Other (OTH) AF: 0.00 AC: 0 AN: 56780

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151844 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74186

African (AFR) AF: 0.00 AC: 0 AN: 41370

American (AMR) AF: 0.0000658 AC: 1 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67870

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000417 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J Pathogenic:1

Jan 16, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN NM_133378: c.30709+1G>A (also known as NM_001267550: c.34612+1G>A) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of TTN function. Loss of function variants in all TTN bands are strongly associated with a spectrum of autosomal recessive titinopathies when exon expression (proportion spliced in, PSI, 1=complete expression) in skeletal muscle is >0.1 (PMID: 36977548, 39198997, 29598826, 32778822, 29691892, 33449170, 36977548, internal data). In contrast, loss of function variants in all TTN bands 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 has a maximum skeletal muscle PSI of 0.582 and a maximum cardiac muscle PSI of 0.2. The variant allele was found at a frequency of 1.6e-05 in 185860 control chromosomes. To our knowledge, no occurrence of c.30709+1G>A in individuals affected with TTN-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. However, it has been reported in at-least two control individuals of European ancestery in the UK Biobank (e.g., Choi_2020). These reports do not provide unequivocal conclusions about association of the variant with TTN-related conditions. The following publication has been ascertained in the context of this evaluation (PMID: 31691645). ClinVar contains an entry for this variant (Variation ID: 404922). Based on the evidence outline above, the variant has been classified as likely pathogenic for autosomal recessive TTN-related conditions. -

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

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 150 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 (rs577363824, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 404922). 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 I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Jul 21, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		5.5
GERP RS		5.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
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

Other links and lift over

dbSNP: rs577363824; hg19: chr2-179539765;