NM_001267550.2:c.38661_38665delGAAAA

Variant names:

• chr2-178653468-GTTTTC-G
• rs1553775212
• NM_001267550.2:c.38661_38665delGAAAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001267550.2(TTN):​c.38661_38665delGAAAA​(p.Lys12887AsnfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.38
• Publications: 2 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-178653468-GTTTTC-G is Pathogenic according to our data. Variant chr2-178653468-GTTTTC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 226126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.38661_38665delGAAAA	p.Lys12887AsnfsTer6	frameshift	Exon 197 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34523-932_34523-928delGAAAA		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.31742-932_31742-928delGAAAA		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.38661_38665delGAAAA	p.Lys12887AsnfsTer6	frameshift	Exon 197 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.38661_38665delGAAAA	p.Lys12887AsnfsTer6	frameshift	Exon 197 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.38385_38389delGAAAA	p.Lys12795AsnfsTer6	frameshift	Exon 195 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.09e-7 AC: 1 AN: 1410622 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 699838

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32554

American (AMR) AF: 0.00 AC: 0 AN: 35474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25328

East Asian (EAS) AF: 0.00 AC: 0 AN: 38646

South Asian (SAS) AF: 0.00 AC: 0 AN: 81346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4036

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096092

Other (OTH) AF: 0.00 AC: 0 AN: 58850

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 27

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 04, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with TTN related disorder (ClinVar ID: VCV000226126). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

not provided Pathogenic:1

Aug 29, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 congenital myopathy who have additional TTN variants (Natera-de Benito et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35628876, 32778822, 28040389, 29575618, 31660661, 33333461)

CAP-congenital myopathy with arthrogryposis multiplex congenita without heart involvement Pathogenic:1

NeuroMeGen, Hospital Clinico Santiago de Compostela

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

TTN-related myopathy Pathogenic:1

May 01, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Lys12887AsnfsTer6 variant in TTN was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 1027852), in two siblings with congenital myopathy. Familial exome analysis showed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 1027852). The p.Lys12887AsnfsTer6 variant in TTN has been previously reported in one individual with autosomal recessive titin-associated myopathy (PMID: 28040389), but has been identified in 0.0008% (2/264690) of chromosomes in TopMed. Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 226126) and has been classified as likely pathogenic by NeuroMeGen,Hospital Clinico Santiago de Compostela. The one affected individual previously reported was homozygous for the variant (PMID: 28040389), which increases the likelihood that the p.Lys12887AsnfsTer6 variant is pathogenic. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 12887 and leads to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive titin-associated myopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive titin-associated myopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Supporting (Richards 2015).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553775212; hg19: chr2-179518195;