Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_001267550.2(TTN):c.104347C>T(p.Leu34783Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000452 in 1,613,850 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L34783L) has been classified as Likely benign.
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]
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, TTN
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.0074152946).
BP6
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BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-178532268-G-A is Benign according to our data. Variant chr2-178532268-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 282653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178532268-G-A is described in Lovd as [Likely_benign]. Variant chr2-178532268-G-A is described in Lovd as [Benign].
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000484 (707/1461570) while in subpopulation SAS AF= 0.00796 (687/86258). AF 95% confidence interval is 0.00747. There are 12 homozygotes in gnomad4_exome. There are 546 alleles in male gnomad4_exome subpopulation. Median coverage is 40. This position pass quality control queck.
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
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not provided Benign:3
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Mar 01, 2023
TTN: BP4, BS2 -
Benign, criteria provided, single submitter
clinical testing
GeneDx
Jul 13, 2018
- -
Likely benign, no assertion criteria provided
clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
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Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Sep 10, 2021
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Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Benign, criteria provided, single submitter
clinical testing
Invitae
Jan 04, 2024
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Cardiomyopathy Benign:1
Benign, criteria provided, single submitter
clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Mar 23, 2018
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Early-onset myopathy with fatal cardiomyopathy Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Sep 10, 2021
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Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Sep 10, 2021
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TTN-related condition Benign:1
Benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Jul 10, 2019
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Tibial muscular dystrophy Benign:1
Benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Sep 10, 2021
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Primary dilated cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter
research
Genetics and Genomics Program, Sidra Medicine
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Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter