ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.95187G>C (p.Trp31729Cys) (rs869320742)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255214 SCV000322335 pathogenic not provided 2016-02-03 criteria provided, single submitter clinical testing The W30088C 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 W30088C impairs the domain solubility and prevents proper protein folding (Hedberg et al., 2014). It was not observed in approximately 6,200 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 W30088C 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. Additionally, this substitution alters a highly conserved position in the 119th fibronectin domain, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants at the same position (W30088L/R) and in nearby residues (P30091L) have been reported in the Human Gene Mutation Database in association with TTN-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, W30088C is considered a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255214 SCV000857525 likely pathogenic not provided 2017-10-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001132648 SCV001292315 uncertain significance Myopathy, early-onset, with fatal cardiomyopathy 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001132649 SCV001292316 uncertain significance Tibial muscular dystrophy 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000119024 SCV001292317 uncertain significance Myopathy, myofibrillar, 9, with early respiratory failure 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001136029 SCV001295847 uncertain significance Dilated cardiomyopathy 1G 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001136030 SCV001295848 uncertain significance Limb-girdle muscular dystrophy, type 2J 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001380728 SCV001578880 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-02-17 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 31729 of the TTN protein (p.Trp31729Cys). There is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of hereditary myopathy with early respiratory failure (HMERF) (PMID: 23606733, 29382405, 29997562, 30666435). This variant is also known as g.274428G>C (p.W30088C) and c.87483G>C (p.Trp29161Cys) in the literature. ClinVar contains an entry for this variant (Variation ID: 132136). 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). This variant has been reported to affect TTN protein function (PMID: 24636144). This variant disrupts the p.Trp31729 (also reported as p.W30088) amino acid residue in TTN. Other variant(s) that disrupt this residue have been observed in individuals with TTN-related conditions (PMID: 23446887, 23606733), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000119024 SCV000153726 pathogenic Myopathy, myofibrillar, 9, with early respiratory failure 2014-02-27 no assertion criteria provided literature only

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