rs141965360
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_001267550.2(TTN):c.64898G>A(p.Arg21633Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,452 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. R21633W) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.64898G>A | p.Arg21633Gln | missense_variant | 310/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2938C>T | non_coding_transcript_exon_variant | 11/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.64898G>A | p.Arg21633Gln | missense_variant | 310/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.417-12853C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000113 AC: 28AN: 248486Hom.: 0 AF XY: 0.000104 AC XY: 14AN XY: 134788
GnomAD4 exome AF: 0.0000527 AC: 77AN: 1461290Hom.: 0 Cov.: 32 AF XY: 0.0000660 AC XY: 48AN XY: 726922
GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74368
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 19, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 08, 2023 | Reported in an infant with sudden unexpected death (Koh et al., 2022); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 26659599, 26934580, 28719003, 17344846, 35027292, 22335739) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 10, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 01, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 15, 2021 | Variant summary: TTN c.57194G>A (p.Arg19065Gln) results in a conservative amino acid change located in the A-band region 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 0.00011 in 248486 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00011 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.57194G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
SUDDEN INFANT DEATH SYNDROME Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Robert's Program, Boston Children's Hospital | Oct 01, 2021 | We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant is a deleterious splicing variant, we suspect this variant is favoring pathogenic. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 01, 2019 | The p.R12568Q variant (also known as c.37703G>A), located in coding exon 137 of the TTN gene, results from a G to A substitution at nucleotide position 37703. The arginine at codon 12568 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at