rs72648278
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_001267550.2(TTN):c.99901G>A(p.Glu33301Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000539 in 1,610,328 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
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.99901G>A | p.Glu33301Lys | missense_variant | Exon 356 of 363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.99901G>A | p.Glu33301Lys | missense_variant | Exon 356 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes 0.000381 AC: 58AN: 152088Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000295 AC: 73AN: 247226Hom.: 0 AF XY: 0.000276 AC XY: 37AN XY: 134112
GnomAD4 exome AF: 0.000555 AC: 810AN: 1458240Hom.: 0 Cov.: 32 AF XY: 0.000517 AC XY: 375AN XY: 724746
GnomAD4 genome 0.000381 AC: 58AN: 152088Hom.: 0 Cov.: 33 AF XY: 0.000350 AC XY: 26AN XY: 74258
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:1
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This variant is associated with the following publications: (PMID: 23396983, 28045975) -
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The TTN c.99901G>A; p.Glu33301Lys variant (rs72648278; ClinVar Variation ID: 47621) is reported in the literature in several individuals affected with HCM or DCM, though it was not demonstrated to cause disease (Franaszczyk 2017, Lopes 2013). This variant has been reported together with TTN variants p.Leu5742Phe and p.Val34563Ala in the literature (Franaszczyk 2017, Lopes 2013) and in another individual tested at ARUP Laboratories. This suggests these three variants may occur in cis, although parental testing would be required to confirm this. This variant is rare in the population (<1% allele frequency in the Genome Aggregation Database) and the clinical relevance of rare missense variants in the TTN 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.Glu33301Lys variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Franaszczyk M et al. Titin Truncating Variants in Dilated Cardiomyopathy - Prevalence and Genotype-Phenotype Correlations. PLoS One. 2017 Jan 3;12(1):e0169007. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. -
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not specified Benign:2
Variant summary: TTN c.92197G>A (p.Glu30733Lys) results in a conservative amino acid change located in the A-band of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 247226 control chromosomes, predominantly at a frequency of 0.00055 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 slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.92197G>A has been reported in the literature in individuals affected with dilated cardiomyopathy or hypertrophic cardiomyopathy. 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. Ten 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 (benign/likely benign n=4, VUS n=6). Based on the evidence outlined above, the variant was classified as likely benign. -
The p.Glu30733Lys variant in TTN is classified as likely benign because it has been identified in 0.06% (76/127160) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, this variant has been identified in at least 1 individual that harbored other disease-causing variants in other cardiomyopathy associated genes (LMM data). ACMG/AMP Criteria applied: BS1, BP5. -
TTN-related disorder Uncertain:1
The TTN c.99901G>A variant is predicted to result in the amino acid substitution p.Glu33301Lys. This variant has been reported in an individual with hypertrophic or dilated cardiomyopathy (referred to as p.E24236K in Table S1, Lopes et al. 2013. PubMed ID: 23396983; Table S4, Franaszczyk et al. 2017. PubMed ID: 28045975). This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, 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 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. -
Hypertrophic cardiomyopathy Uncertain:1
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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
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