rs869320739
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5
The NM_001267550.2(TTN):c.95126C>G(p.Pro31709Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31709H) 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.95126C>G | p.Pro31709Arg | missense_variant | 343/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2043+3749G>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.95126C>G | p.Pro31709Arg | missense_variant | 343/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.416+22474G>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 21, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 29, 2016 | The P29141R missense variant in the TTN gene has been reported previously in association with autosomal dominant hereditary myopathy with early respiratory failure (HMERF) (Palmio et al., 2014). Functional studies indicate that P29141R impairs the domain solubility and prevents proper protein folding (Hedberg et al., 2014). In these studies, the P29141R variant was reported as P30068R due to the use of alternative nomenclature. The P29141R variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P29141R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position predicted to be within the 119th fibronectin domain, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, P29141R is considered a pathogenic variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 06, 2015 | - - |
Myopathy, myofibrillar, 9, with early respiratory failure Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 13, 2023 | The TTN c.95126C>G (p.Pro31709Arg) missense variant results in the substitution of proline at amino acid position 31709 with arginine. This variant, sometimes referred to in the literature as c.90203C>G (p.Pro30068Arg), has been reported in a heterozygous state in two related individuals with myofibrillar myopathy with early respiratory failure (PMID: 23606733). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant is located in exon 343 of TTN, within the 119th fibronectin III domain of the titin A band motif, which is where all disease -causing variants have been located to date(PMID: 24575448). Functional studies in E. coli suggest that the c.95126C>G variant impairs domain solubility and prevents protein folding (PMID: 24636144). Another variant at the same position (c.95126C>A; p.Pro31709His) has been reported in an individual with myofibrillar myopathy with early respiratory failure (PMID: 30666435). Based on the available evidence, the c.95126C>G (p.Pro31709Arg) variant is classified as likely pathogenic for myofibrillar myopathy with early respiratory failure. - |
Pathogenic, no assertion criteria provided | literature only | GeneReviews | Feb 27, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at