rs200689750
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001267550.2(TTN):āc.62572A>Gā(p.Thr20858Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000565 in 1,613,320 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.62572A>G | p.Thr20858Ala | missense_variant | Exon 304 of 363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.62572A>G | p.Thr20858Ala | missense_variant | Exon 304 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes 0.000276 AC: 42AN: 152094Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000407 AC: 101AN: 248280 AF XY: 0.000408 show subpopulations
GnomAD4 exome AF: 0.000595 AC: 870AN: 1461108Hom.: 2 Cov.: 32 AF XY: 0.000586 AC XY: 426AN XY: 726864 show subpopulations
Age Distribution
GnomAD4 genome 0.000276 AC: 42AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74406 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:6
This variant is associated with the following publications: (PMID: 23861362) -
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not specified Uncertain:1Benign:2
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Variant summary: TTN c.54868A>G (p.Thr18290Ala) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 248280 control chromosomes (gnomAD), predominantly at a frequency of 0.00081 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 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 Non-Finnish European origin. c.54868A>G has been reported in the literature in individuals affected with long QT syndrome (Campuzano_2015) and co-occuring with a truncting TTN variant in an individual with Dilated Cardiomyopathy (Fomin_2021). These reports do 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. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 34731013). Nine ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, two as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Variant classified as Uncertain Significance - Favor Benign. The Thr18290Ala var iant in TTN has not been reported in the literature nor previously identified by our laboratory. This variant has been identified in 0.1% (9/8240) of European A merican chromosomes from a broad population by the NHLBI Exome Sequencing Projec t (http://evs.gs.washington.edu/EVS). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide st rong support for or against an impact to the protein. In summary, the frequency of this variant suggests that it is more likely benign, but it is too low to con fidently rule out a disease-causing role. Additional information is needed to fu lly assess the clinical significance of this variant. -
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. -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
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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. -
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. -
Cardiomyopathy Benign:1
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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. -
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. -
Cardiovascular phenotype Benign:1
In silico models in agreement (benign);Subpopulation frequency in support of benign classification -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at