rs761362832
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_001267550.2(TTN):c.99518G>A(p.Cys33173Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. C33173S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.99518G>A | p.Cys33173Tyr | missense_variant | 355/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.645C>T | splice_region_variant, non_coding_transcript_exon_variant | 4/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.99518G>A | p.Cys33173Tyr | missense_variant | 355/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.416+14053C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152152Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000522 AC: 13AN: 248920Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135038
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461474Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20AN XY: 727010
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74318
ClinVar
Submissions by phenotype
not provided Uncertain:3Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 24, 2020 | - - |
not provided, no classification provided | clinical testing | GeneDx | Jun 03, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 12, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | TTN: PP3 - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 02, 2020 | Variant summary: TTN c.91814G>A (p.Cys30605Tyr) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 248920 control chromosomes, predominantly at a frequency of 0.00032 within the Latino subpopulation in the gnomAD database (exomes dataset). This frequency is somewhat lower than the maximum expected for a pathogenic variant in TTN causing Cardiomyopathy (0.00032 vs 0.00063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.91814G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 06, 2020 | The c.91814G>A sequence change results in an amino acid change, p.Cys30605Tyr. This sequence change has been described in the gnomAD database with a low population frequency of 0.005223% (dbSNP rs761362832). The p.Cys30605Tyr change affects a highly conserved amino acid residue located in a domain of the TTN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys30605Tyr substitution. This sequence change does not appear to have been previously described in patients with TTN-related disorders. Due to the lack of sufficient evidence, the clinical significance of the p.Cys30605Tyr change remains unknown at this time. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2017 | - - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Dec 24, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at