rs869320740
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PP5_Very_Strong
The NM_001267550.2(TTN):āc.95134T>Cā(p.Cys31712Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,455,650 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C31712W) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.95134T>C | p.Cys31712Arg | missense_variant | 343/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2043+3741A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.95134T>C | p.Cys31712Arg | missense_variant | 343/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.416+22466A>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000411 AC: 1AN: 243382Hom.: 0 AF XY: 0.00000758 AC XY: 1AN XY: 131866
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1455650Hom.: 0 Cov.: 33 AF XY: 0.00000415 AC XY: 3AN XY: 723540
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 31, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2020 | Published functional studies demonstrate a that C30071R impairs solubility of the 119th fibronectin-3 domain, causing defective protein folding (Hedberg et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32039858, 27854229, 22577215, 24636144, 24444549, 29435569, 23514108, 25500009, 22577218, 30666435, 24980681, 24575448, 26518445, 26269091, 25253871, 32403337, 32307395) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 08, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | TTN: PP1:Strong, PM1, PM2, PM5, PP4, PS4:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 27, 2017 | - - |
Myopathy, myofibrillar, 9, with early respiratory failure Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2014 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The TTN c.95134T>C variant has been reported in heterozygous state in individuals affected with Myopathy, myofibrillar, 9, with early respiratory failure (Chauveau et. al., 2014; Pfeffer et. al., 2014). It is a common cause of HMERF in individuals of many different ancestries (Pfeffer et. al., 2014, Yue et. al., 2015). Experimental studies have found that this missense change may interfere with the proper folding of the fibronectin III domain 119 of the TTN protein (Hedberg et. al., 2014). This variant has been reported to the ClinVar database as Pathogenic. The p.Cys31712Arg variant is novel (not in any individuals) in 1000 Genomes and has an allele frequency of 0.0004109% in gnomAD database. The amino acid Cys at position 31712 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | This variant is also known as g.274375T4C (p.Cys30071Arg). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 31712 of the TTN protein (p.Cys31712Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant hereditary myopathy with early respiratory failure (HMERF) (PMID: 24444549, 24980681, 25500009). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 132133). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects TTN function (PMID: 24636144). 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). For these reasons, this variant has been classified as Pathogenic. - |
Dilated cardiomyopathy 1G Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 23, 2017 | - - |
Hypertrophic cardiomyopathy 9 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.80). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000132133) and a different missense change at the same codon (p.Cys31712Tyr) has been reported to be associated with TTN related disorder (PMID: 25253871). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23514108, 24444549, 25500009). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at