rs72648989
Variant summary
Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001267550.2(TTN):āc.26494A>Gā(p.Ile8832Val) variant causes a missense change. The variant allele was found at a frequency of 0.00139 in 1,610,370 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. I8832T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Benign. The variant received -13 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.26494A>G | p.Ile8832Val | missense_variant | Exon 92 of 363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.26494A>G | p.Ile8832Val | missense_variant | Exon 92 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes 0.000802 AC: 122AN: 152156Hom.: 1 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000773 AC: 190AN: 245890 AF XY: 0.000788 show subpopulations
GnomAD4 exome AF: 0.00146 AC: 2124AN: 1458096Hom.: 3 Cov.: 34 AF XY: 0.00145 AC XY: 1052AN XY: 724898 show subpopulations
Age Distribution
GnomAD4 genome 0.000801 AC: 122AN: 152274Hom.: 1 Cov.: 33 AF XY: 0.000793 AC XY: 59AN XY: 74444 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:5
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This variant is associated with the following publications: (PMID: 23396983, 23861362) -
TTN: BP4 -
The TTN c.26494A>G; p.Ile8832Val variant (rs72648989; ClinVar Variation ID: 177972) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Ile8832Val variant cannot be determined with certainty. -
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not specified Uncertain:2Benign:2
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Variant classified as Uncertain Significance - Favor Benign. The Ile7588Val vari ant in TTN has been identified by our laboratory in 1 Caucasian adult with HCM w ho also carried a pathogenic variant in another gene and 1 adult of unspecified ethnicity with DCM. This variant has been also been identified in 0.1% (8/8156) of European American chromosomes by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS/, Ng 2013; dbSNP rs72648989). Computational prediction tools and conservation analysis suggest that the Ile7588Val variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. In addition, 1 fish (yellowbelly pufferfish) carries a valine at thi s position, raising the possibility that this change may be tolerated. In summar y, while the clinical significance of the Ile7588Val variant is uncertain, its f requency in controls suggests that it is more likely to be benign. -
Variant summary: TTN c.22762A>G (p.Ile7588Val) results in a conservative amino acid change located in the I-Band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 245890 control chromosomes. The observed variant frequency is approximately 1.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. c.22762A>G has been reported in the literature without strong evidence for causality (Campuzano_2015, Mademont-Soler_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 (3 VUS, 2 likely benign). Based on the evidence outlined above, the variant was classified as likely benign. -
Distal myopathy Uncertain:1
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Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Dilated cardiomyopathy 1G Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Cardiomyopathy Uncertain:1
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Early-onset myopathy with fatal cardiomyopathy Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Limb-girdle muscular dystrophy Uncertain:1
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TTN-related disorder Benign:1
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
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Tibial muscular dystrophy Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at