2-178597908-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP2PP3_Strong
The NM_001267550.2(TTN):c.57262G>T(p.Val19088Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000434 in 1,612,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V19088I) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.57262G>T | p.Val19088Phe | missense_variant, splice_region_variant | 293/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.3450+227C>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.57262G>T | p.Val19088Phe | missense_variant, splice_region_variant | 293/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.502+227C>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152020Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248148Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134628
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460822Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 726660
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152020Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74240
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 24, 2014 | The p.Val16520Phe variant in TTN has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. This variant is located in the last three bases of the exon, which is part of the 5? splice r egion. Computational tools suggest an impact to splicing; however, this informat ion is not predictive enough to determine pathogenicity. In summary, the clinica l significance of the p.Val16520Phe variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2013 | Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM panel(s). - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 24, 2022 | This sequence change replaces valine with phenylalanine at codon 19088 of the TTN protein (p.Val19088Phe). There is a small physicochemical difference between valine and phenylalanine. This variant also falls at the last nucleotide of exon 293, which is part of the consensus splice site for this exon. This variant is present in population databases (rs727505347, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 180098). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 20, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at