NM_001267550.2:c.94553T>C
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6
The NM_001267550.2(TTN):āc.94553T>Cā(p.Val31518Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,594,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: Likely_benign. The variant received -2 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | MANE Select | c.94553T>C | p.Val31518Ala | missense | Exon 341 of 363 | NP_001254479.2 | ||
| TTN | NM_001256850.1 | c.89630T>C | p.Val29877Ala | missense | Exon 291 of 313 | NP_001243779.1 | |||
| TTN | NM_133378.4 | c.86849T>C | p.Val28950Ala | missense | Exon 290 of 312 | NP_596869.4 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | TSL:5 MANE Select | c.94553T>C | p.Val31518Ala | missense | Exon 341 of 363 | ENSP00000467141.1 | ||
| TTN | ENST00000446966.2 | TSL:1 | c.94397T>C | p.Val31466Ala | missense | Exon 339 of 361 | ENSP00000408004.2 | ||
| TTN | ENST00000436599.2 | TSL:1 | c.94277T>C | p.Val31426Ala | missense | Exon 339 of 361 | ENSP00000405517.2 |
Frequencies
GnomAD3 genomes 0.000230 AC: 35AN: 152158Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000135 AC: 32AN: 236804 AF XY: 0.000117 show subpopulations
GnomAD4 exome AF: 0.000326 AC: 470AN: 1442594Hom.: 0 Cov.: 33 AF XY: 0.000337 AC XY: 241AN XY: 714408 show subpopulations
Age Distribution
GnomAD4 genome 0.000230 AC: 35AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74334 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
This variant is associated with the following publications: (PMID: 23396983, 30847666)
not specified Uncertain:1Benign:1
Variant summary: TTN c.86849T>C (p.Val28950Ala) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 1594752 control chromosomes, predominantly at a frequency of 0.00041 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 equal to the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039). c.86849T>C has been reported in the literature in individuals affected with Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy, without strong evidence for causality (e.g. Lopes, van Lint_2019, Minoche_2019). 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: 23396983, 29961767, 30847666). ClinVar contains an entry for this variant (Variation ID: 203005). Based on the evidence outlined above, the variant was classified as likely benign.
The p.Val28950Ala variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 9/64750 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s377016580). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Val28950Ala variant is uncertain.
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.
TTN-related disorder Uncertain:1
The TTN c.94553T>C variant is predicted to result in the amino acid substitution p.Val31518Ala. This variant has been reported in compound heterozygous state in individuals with dilated cardiomyopathy, however no information was provided to establish its pathogenicity (Supplementary file 2 in case 1463, van Lint et al. 2019. PubMed ID: 30847666; Minoche et al. 2018. PubMed ID: 29961767). This variant is reported in 0.030% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
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.
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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at