rs587782988

chr2-178595498-TTTAC-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001267550.2(TTN):c.57847+5_57847+8del variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000215 in 1,393,550 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: TTN NM_001267550.2 splice_donor_5th_base, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 6.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.57847+5_57847+8del		splice_donor_5th_base_variant, intron_variant		ENST00000589042.5
TTN-AS1	NR_038272.1	n.3365-2090_3365-2087del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.57847+5_57847+8del		splice_donor_5th_base_variant, intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.417-2090_417-2087del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1393550 Hom.: 0 AF XY: 0.00000291 AC XY: 2 AN XY: 687154

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 25, 2023

This sequence change falls in intron 295 of the TTN gene. It does not directly change the encoded amino acid sequence of the TTN protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 28416588). ClinVar contains an entry for this variant (Variation ID: 155850). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). 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. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 17, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2019

Reported in an individual with DCM (Dal Ferro et al., 2017); Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 155850; Landrum et al., 2016); Occurs within the consensus splice donor site; in silico analysis, including splice predictors and evolutionary conservation, suggests this variant damages the splice donor site of intron 245 and predicts it will cause abnormal gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 28416588) -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Jan 29, 2014

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.30652+5_30652+8delGTAA intronic variant, located in intron 122 of the TTN gene, results from a deletion of 4 nucleotides within intron 122 of the TTN gene. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Dal Ferro M et al. Heart, 2017 Nov;103:1704-1710). This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.67		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587782988; hg19: chr2-179460225;