chr2-178779001-T-G
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BP6
The NM_001267550.2(TTN):āc.4081A>Cā(p.Ile1361Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000193 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1361V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.4081A>C | p.Ile1361Leu | missense_variant | 24/363 | ENST00000589042.5 | |
TTN | NM_133379.5 | c.4081A>C | p.Ile1361Leu | missense_variant | 24/46 | ENST00000360870.10 | |
LOC101927055 | NR_120594.1 | n.1830+246T>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.4081A>C | p.Ile1361Leu | missense_variant | 24/363 | 5 | NM_001267550.2 | P1 | |
TTN | ENST00000360870.10 | c.4081A>C | p.Ile1361Leu | missense_variant | 24/46 | 5 | NM_133379.5 | ||
TTN-AS1 | ENST00000659121.1 | n.6182+246T>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152132Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000638 AC: 16AN: 250706Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135474
GnomAD4 exome AF: 0.000207 AC: 303AN: 1461728Hom.: 0 Cov.: 30 AF XY: 0.000191 AC XY: 139AN XY: 727180
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152132Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74316
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 19, 2022 | BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 07, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 21, 2022 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 12, 2024 | Variant summary: TTN c.4081A>C (p.Ile1361Leu) results in a conservative amino acid change located in the near Z-disk region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 1613860 control chromosomes, predominantly at a frequency of 0.00025 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00025 vs 0.00039), allowing no conclusion about variant significance. c.4081A>C has been reported in the literature as a VUS in a setting of multigene panel testing in an individual affected with Dilated Cardiomyopathy (Burstein_2021). 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. ClinVar contains an entry for this variant (Variation ID: 229444). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 20, 2015 | The p.Ile1361Leu variant in TTN has been identified by our laboratory in 1 Black adolescent with DCM and in 1/66602 European chromosomes and 1/10390 African chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs145308734). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summa ry, the clinical significance of the p.Ile1361Leu variant is uncertain. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2017 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 28, 2020 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at