ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.95126C>G (p.Pro31709Arg)

dbSNP: rs869320739
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255564 SCV000322333 pathogenic not provided 2016-07-29 criteria provided, single submitter clinical testing 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.
Revvity Omics, Revvity RCV000255564 SCV002021538 likely pathogenic not provided 2019-02-21 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000119020 SCV004014712 likely pathogenic Myopathy, myofibrillar, 9, with early respiratory failure 2023-03-13 criteria provided, single submitter clinical testing 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.
GeneReviews RCV000119020 SCV000153722 pathogenic Myopathy, myofibrillar, 9, with early respiratory failure 2014-02-27 no assertion criteria provided literature only
Eurofins Ntd Llc (ga) RCV000255564 SCV000333717 uncertain significance not provided 2015-08-06 flagged submission clinical testing

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