rs573843615

Variant names:

• chr2-178531098-CAGA-C
• rs573843615
• NM_001267550.2:c.105514_105516delTCT

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_Supporting BP6

The NM_001267550.2(TTN):​c.105514_105516delTCT​(p.Ser35172del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: TTN NM_001267550.2 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:4
• Conservation: PhyloP100: 8.00

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 0 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001267550.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-178531098-CAGA-C is Benign according to our data. Variant chr2-178531098-CAGA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180582.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=9}. Variant chr2-178531098-CAGA-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.105514_105516delTCT	p.Ser35172del	conservative_inframe_deletion	Exon 358 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.105514_105516delTCT	p.Ser35172del	conservative_inframe_deletion	Exon 358 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000309 AC: 77 AN: 249180 Hom.: 0 AF XY: 0.000318 AC XY: 43 AN XY: 135178

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000511

Gnomad NFE exome AF: 0.000522

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000332 AC: 486 AN: 1461698 Hom.: 0 AF XY: 0.000369 AC XY: 268 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.000390

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74346

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000227

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

Jun 09, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32880476) -

Aug 31, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: PM4:Supporting -

Feb 24, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Sep 27, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser32604del variant (rs573843615) has not been reported in the medical literature nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 180582). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans of 0.056% (identified in 71 out of 126,608 chromosomes). This variant is an in-frame deletion of a single amino acid in a non-repeat region of TTN protein, and the consequences on protein structure/function are not predictable. Thus, based on the available information, the clinical significance of the p.Ser32604del variant cannot be determined with certainty. -

TTN-related disorder Uncertain:1

Mar 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TTN c.105514_105516delTCT variant is predicted to result in an in-frame deletion (p.Ser35172del). This variant was reported along with a second TTN variant (p.Arg15327Cys) in one patient and along with a nonsense NEXN variant in a second patient in a study of individuals with dilated cardiomyopathy (Table S4, Verdonschot et al. 2020. PubMed ID: 32880476). This variant is reported in 0.056% of alleles in individuals of European (Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Dec 27, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Uncertain:1

Jul 16, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Uncertain:1

Feb 16, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM4. -

Myopathy, myofibrillar, 9, with early respiratory failure Uncertain:1

Apr 05, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Left ventricular noncompaction cardiomyopathy Uncertain:1

Aug 28, 2014

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Nov 21, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN c.97810_97812delTCT (p.Ser32604del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 0.00031 in 249180 control chromosomes, predominantly at a frequency of 0.00052 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.33 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.97810_97812delTCT has been reported in the literature in a DCM cohort listed as a VUS (Verdonschot_2020). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: six submitters classified the variant as VUS while 2 classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype Benign:1

Apr 10, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypertrophic cardiomyopathy 1 Benign:1

Mar 15, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The TTN Ser35172del is an in-frame deletion. This variant is located in the M-band where truncating variants have been associated with DCM. TTN Ser35172del has been observed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.0003. We have identified this variant in an HCM case. An additional variant (MYH7 Arg652Gly) was also identified in this individual which is sufficient to explain disease. Given the limited understanding of TTN in-frame deletions particularly in HCM cases, the higher than expected frequency in ExAC, and that another possibly disease-causing variant has been identified in our case, we have classified this as a likely benign variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs573843615; hg19: chr2-179395825;