2-178677741-TTTCCTCTTCTTCAGGTAGAACTTCCTCTTCTTCAGGTAGAAC-TTTCCTCTTCTTCAGGTAGAAC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BP6 BS2

The NM_001267550.2(TTN):c.34150_34170del(p.Val11384_Glu11390del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000725 in 151,708 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 0.00073 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (9 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 6.13

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_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001267550.2.
• BP6: Variant 2-178677741-TTTCCTCTTCTTCAGGTAGAAC-T is Benign according to our data. Variant chr2-178677741-TTTCCTCTTCTTCAGGTAGAAC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130665.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=5, Likely_benign=3}. Variant chr2-178677741-TTTCCTCTTCTTCAGGTAGAAC-T is described in Lovd as [Benign]. Variant chr2-178677741-TTTCCTCTTCTTCAGGTAGAAC-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.34150_34170del	p.Val11384_Glu11390del	inframe_deletion	146/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+33271_2185+33291del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.34150_34170del	p.Val11384_Glu11390del	inframe_deletion	146/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.503-56732_503-56712del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000732 AC: 111 AN: 151590 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000593

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.00354

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000959

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00133 AC: 330 AN: 248956 Hom.: 4 AF XY: 0.00163 AC XY: 220 AN XY: 135048

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00117

Gnomad SAS exome AF: 0.00566

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000904

Gnomad OTH exome AF: 0.00149

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00135 AC: 1979 AN: 1460714 Hom.: 9 AF XY: 0.00151 AC XY: 1098 AN XY: 726634

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.000731

Gnomad4 SAS exome AF: 0.00456

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.000725 AC: 110 AN: 151708 Hom.: 0 Cov.: 31 AF XY: 0.000701 AC XY: 52 AN XY: 74160

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.000592

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.00334

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000959

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000395 Hom.: 0

EpiCase AF: 0.000764

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 02, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	TTN: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 02, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 20, 2021	Variant summary: TTN c.30418_30438del21 (p.Val10140_Glu10146del) results in an in-frame deletion that is predicted to remove seven amino acids from the encoded protein. The variant allele was found at a frequency of 0.0013 in 248956 control chromosomes, predominantly at a frequency of 0.0057 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.30418_30438del21 in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1), likely benign (n=4) and benign(n=1). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 14, 2020	The p.Val10140_Glu10146del variant in TTN is classified as benign because it has been identified in 0.56% (173/30572) of South Asian chromosomes, including 4 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Arrhythmogenic right ventricular dysplasia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jan 30, 2019

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

-

- -

TTN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jan 22, 2019

- -

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: rs587780487; hg19: chr2-179542468;