rs727504205
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_001267550.2(TTN):c.24891G>T(p.Trp8297Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.24891G>T | p.Trp8297Cys | missense_variant | 86/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.24891G>T | p.Trp8297Cys | missense_variant | 86/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.503-16389C>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459796Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 726320
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 22, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 27, 2023 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 8297 of the TTN protein (p.Trp8297Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy and/or congenital myopathy (PMID: 32528171, 33146414; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.21159G>T p.W7053C. ClinVar contains an entry for this variant (Variation ID: 167799). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located in the I band of TTN (PMID: 25589632). Non-truncating variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). 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 | Baylor Genetics | Sep 01, 2017 | This variant was found once in our laboratory In trans with a frameshift variant in an 8-year-old male with congenital myopathy, hypotonia, hyperextensibility, scapular winging, weakness, joint laxity, ankle contractures, type I fiber predominance on muscle biopsy, family history of a brother with a similar phenotype (also compound heterozygous) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at