rs761617432

Positions:

• chr2-178653473-CT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_001267550.2(TTN):​c.38660del​(p.Lys12887ArgfsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000803 in 149,438 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00015 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 0.166

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

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.38660del	p.Lys12887ArgfsTer60	frameshift_variant	197/363	ENST00000589042.5	NP_001254479.2
LOC124906100	XR_007087318.1	n.2185+8976del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.38660del	p.Lys12887ArgfsTer60	frameshift_variant	197/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.502+55796del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000803 AC: 12 AN: 149438 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000178

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000112 AC: 10 AN: 89040 Hom.: 0 AF XY: 0.0000835 AC XY: 4 AN XY: 47922

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: 0.000242

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000154 AC: 217 AN: 1407222 Hom.: 1 Cov.: 32 AF XY: 0.000153 AC XY: 107 AN XY: 697940

Gnomad4 AFR exome AF: 0.0000308

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: 0.000189

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.0000803 AC: 12 AN: 149438 Hom.: 0 Cov.: 27 AF XY: 0.0000688 AC XY: 5 AN XY: 72652

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000178

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000742 Hom.: 0

Bravo AF: 0.0000831

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Located in a region of TTN in which the majority of pathogenic variants have been reported in association with autosomal recessive titinopathies (Fernandez-Marmiesse et al., 2017; Chervinsky et al., 2018; Bryen, et al., 2020; Savarese et al., 2020); Identified in patients with arthrogryposis who have additional TTN variants, though it is unclear if the variants were confirmed to be on opposite alleles (in trans) in each patient (Ravenscroft et al., 2020); This variant is associated with the following publications: (PMID: 33820833, 35580751, 28040389, 29575618, 31660661, 32778822, 33060286) -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 14, 2017

In summary, this truncating variant is found in the I-band of the TTN protein where truncating variants have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739, 25589632). However, truncating variants in the I-band have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons it has been classified as a Variant of Uncertain Significance. While this variant is present in population databases (rs761617432), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a TTN-related disease. This sequence change deletes 1 nucleotide from exon 197 of the TTN mRNA (c.38660delA), causing a frameshift at codon 12887. This creates a premature translational stop signal in exon 197 of the TTN mRNA (p.Lys12887Argfs*60). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated TTN protein. -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs761617432; hg19: chr2-179518200;