rs558487304
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_001267550.2(TTN):c.49016G>A(p.Arg16339Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000168 in 1,610,110 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16339W) has been classified as Likely benign.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.49016G>A | p.Arg16339Gln | missense_variant | 261/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.49016G>A | p.Arg16339Gln | missense_variant | 261/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.502+16817C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151836Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000203 AC: 5AN: 246374Hom.: 0 AF XY: 0.0000225 AC XY: 3AN XY: 133590
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1458274Hom.: 0 Cov.: 34 AF XY: 0.0000221 AC XY: 16AN XY: 725080
GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151836Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74120
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2014 | 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-CRDM 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 | Jul 22, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 16339 of the TTN protein (p.Arg16339Gln). This variant is present in population databases (rs558487304, gnomAD 0.01%). 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: 202672). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at