Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBP6_Very_Strong
The NM_001267550.2(TTN):āc.62149A>Gā(p.Arg20717Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000104 in 1,613,438 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ). Synonymous variant affecting the same amino acid position (i.e. R20717R) 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]
Missense variant where missense usually causes diseases, TTN
BP4
Computational evidence support a benign effect (MetaRNN=0.014564544).
BP6
Variant 2-178589576-T-C is Benign according to our data. Variant chr2-178589576-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 467346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178589576-T-C is described in Lovd as [Likely_benign].
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Jun 28, 2019
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Likely benign, criteria provided, single submitter
clinical testing
Athena Diagnostics
Mar 28, 2018
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not specified Benign:1
Benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Apr 04, 2024
Variant summary: TTN c.54445A>G (p.Arg18149Gly) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 1606474 control chromosomes, predominantly at a frequency of 0.0034 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. In addition, the variant was also reported in 1 homozygote in healthy Japanese individuals in the jMorp database [PMID: 33179747]. The relatively high allele frequency in East Asians, together with the occurrences in homozygotes suggests that the variant could be a benign polymorphism. To our knowledge, no occurrence of c.54445A>G in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 467346). Based on the evidence outlined above, the variant was as benign. -
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
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 29, 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
Jan 31, 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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Tibial muscular dystrophy 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