rs794729338
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001267550.2(TTN):c.71980_71986delinsTA(p.Ala23994Ter) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A23994A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001267550.2 stop_gained, frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.71980_71986delinsTA | p.Ala23994Ter | stop_gained, frameshift_variant | 326/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2044-8426_2044-8420delinsTA | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.71980_71986delinsTA | p.Ala23994Ter | stop_gained, frameshift_variant | 326/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.417-23450_417-23444delinsTA | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; 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: 26315439, 30609409, 22335739) - |
Primary dilated cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 22, 2018 | The p.Ala21426X (NM_133432.3 c.64276_64282delinsTA) variant in TTN (also reporte d as c.67057_67063delGCATATGinsTA p.Ala22353fs in the literature) has been prev iously reported in 1 heterozygous proband with dilated cardiomyopathy (DCM) and segregated with disease in 10 family members (7 confirmed to have the variant an d 3 obligate carriers) (Herman 2012). This variant has also been reported as pat hogenic in ClinVar (ClinVar#202465; NM_001256850.1: p.Ala22353Terfs), and was ab sent from large population studies, though the ability of these studies to accur ately detect indels may be limited. This variant leads to a premature terminatio n codon at position 21426, which is predicted to lead to a truncated or absent p rotein. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Robe rts 2015), both of which are true for this variant. In addition, pathogenic vari ants in TTN, when found on both copies of the gene, are associated with recessiv e centronuclear myopathy. In summary, this variant meets criteria to be classi fied as pathogenic for DCM in an autosomal dominant manner based upon a predicte d null effect and its segregation in affected individuals, as well as likely pat hogenic for centronuclear myopathy in a recessive manner. - |
Centronuclear myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 22, 2018 | The p.Ala21426X (NM_133432.3 c.64276_64282delinsTA) variant in TTN (also reporte d as c.67057_67063delGCATATGinsTA p.Ala22353fs in the literature) has been prev iously reported in 1 heterozygous proband with dilated cardiomyopathy (DCM) and segregated with disease in 10 family members (7 confirmed to have the variant an d 3 obligate carriers) (Herman 2012). This variant has also been reported as pat hogenic in ClinVar (ClinVar#202465; NM_001256850.1: p.Ala22353Terfs), and was ab sent from large population studies, though the ability of these studies to accur ately detect indels may be limited. This variant leads to a premature terminatio n codon at position 21426, which is predicted to lead to a truncated or absent p rotein. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Robe rts 2015), both of which are true for this variant. In addition, pathogenic vari ants in TTN, when found on both copies of the gene, are associated with recessiv e centronuclear myopathy. In summary, this variant meets criteria to be classi fied as pathogenic for DCM in an autosomal dominant manner based upon a predicte d null effect and its segregation in affected individuals, as well as likely pat hogenic for centronuclear myopathy in a recessive manner. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at