rs281864927

Variant names:

• chr2-178527198-CCATGTTACTT-TTTTTCTTTCA
• rs281864927
• NM_001267550.2:c.107780_107790delAAGTAACATGGinsTGAAAGAAAAA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001267550.2(TTN):​c.107780_107790delAAGTAACATGGinsTGAAAGAAAAA​(p.GluValThrTrp35927ValLysGluLys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 2-178527198-CCATGTTACTT-TTTTTCTTTCA is Pathogenic according to our data. Variant chr2-178527198-CCATGTTACTT-TTTTTCTTTCA is described in ClinVar as [Pathogenic]. Clinvar id is 12652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.107780_107790delAAGTAACATGGinsTGAAAGAAAAA	p.GluValThrTrp35927ValLysGluLys	missense_variant		ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.107780_107790delAAGTAACATGGinsTGAAAGAAAAA	p.GluValThrTrp35927ValLysGluLys	missense_variant		5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Sep 11, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 24, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality (0/248952 chr). Found in at least one symptomatic patient. Statistically associated with disease in multiple families. (p < 0.05) -

Nov 29, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 24, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Genetics and Personalized Medicine Clinic, Tartu University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We found in compound heterozygous state in trans with splicing variant NM_001267550.2(TTN):c.64672+2dup in two patients with Titin-related limb-girdle muscular dystrophy R10 and in monoallelic state in family members with tibial muscular dystrophy. -

Tibial muscular dystrophy Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 24, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Oct 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.107780_107790delinsTGAAAGAAAAA, is a complex sequence change that results in the deletion of 4 and insertion of 4 amino acid(s) in the TTN protein (p.Glu35927_Trp35930delinsValLysGluLys). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individuals with autosomal dominant tibial muscular dystrophy and autosomal recessive limb-girdle muscular dystrophy in many families (PMID: 12145747, 15728284, 24395473). It is commonly reported in individuals of Finnish ancestry (PMID: 12145747, 15728284, 24395473). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TTN function (PMID: 24395473, 25589632, 25739468). This variant is located in the M band of TTN (PMID: 25589632). Non-truncating variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Pathogenic:1

Jul 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Aug 23, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.80585_80595del11ins11 pathogenic mutation (also known as p.E26862_W26865delinsVKEK), located in coding exon 190 of the TTN gene, results from an in-frame deletion of AAGTAACATGG and insertion of TGAAAGAAAAA at nucleotide positions 80585 to 80595. This results in the in-frame deletion of four amino acids (EVTW) and insertion of four amino acids (VKEK) at codons 26862 to 26865. This exon is located in the M-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This variant (also referred to as FINmaj, and p.E33359_W33362delinsVKEK) has been reported as a Finnish founder mutation in numerous individuals across multiple families affected with phenotypes consistent with autosomal dominant tibial muscular dystrophy in the heterozygous state and autosomal recessive limb-girdle muscular dystrophy in the homozygous state, and has also been reported in the compound heterozygous state with other TTN variants in individuals with various myopathy phenotypes (Hackman P et al. Am J Hum Genet. 2002 Sep;71(3):492-500; Udd B et al. Neurology. 2005 Feb;64(4):636-42; Hackman P et al. Neuromuscul Disord. 2008 Dec;18(12):922-8; Evil&auml; A et al. Ann Neurol. 2014 Feb;75(2):230-40; Sainio MT et al. Acta Neurol Scand. 2022 Jan;145(1):63-72). In one case, this variant was heterozygous in an individual reported to have skeletal myopathy and cardiomyopathy; however, details were limited (Sainio MT et al. Acta Neurol Scand. 2022 Jan;145(1):63-72). In assays testing protein function, this variant showed functionally abnormal results (Sarparanta J et al. J Biol Chem. 2010 Sep;285(39):30304-15; Rudloff MW et al. Protein Sci. 2015 Jun;24(6):946-55). This amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is pathogenic in association with autosomal dominant tibial muscular dystrophy and autosomal recessive limb-girdle muscular dystrophy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs281864927; hg19: chr2-179391925;