ClinVar Genomic variation as it relates to human health
NM_001267550.2(TTN):c.95195C>T (p.Pro31732Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001267550.2(TTN):c.95195C>T (p.Pro31732Leu)
Variation ID: 132137 Accession: VCV000132137.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q31.2 2: 178546041 (GRCh38) [ NCBI UCSC ] 2: 179410768 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 24, 2015 Apr 15, 2024 Mar 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001267550.2:c.95195C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001254479.2:p.Pro31732Leu missense NM_001256850.1:c.90272C>T NP_001243779.1:p.Pro30091Leu missense NM_001267550.1:c.95195C>T NM_003319.4:c.68000C>T NP_003310.4:p.Pro22667Leu missense NM_133378.4:c.87491C>T NP_596869.4:p.Pro29164Leu missense NM_133432.3:c.68375C>T NP_597676.3:p.Pro22792Leu missense NM_133437.4:c.68576C>T NP_597681.4:p.Pro22859Leu missense NC_000002.12:g.178546041G>A NC_000002.11:g.179410768G>A NG_011618.3:g.289762C>T NG_051363.1:g.28215G>A LRG_391:g.289762C>T - Protein change
- P31732L, P29164L, P22792L, P22859L, P30091L, P22667L
- Other names
- Q8WZ42.4:p.Pro30091Leu
- Canonical SPDI
- NC_000002.12:178546040:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TTN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
11682 | 30988 | |
TTN-AS1 | - | - | - | GRCh38 | - | 17716 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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not provided (1) |
no classification provided
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- | RCV000119025.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 22, 2023 | RCV000684823.7 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2023 | RCV000727672.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 14, 2021 | RCV002492403.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 16, 2023 | RCV003343647.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 9, 2024 | RCV003987364.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 25, 2024 | RCV003988827.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446810.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Microcephaly (present) , Hypotonia (present) , Flexion contracture (present) , Respiratory insufficiency (present) , Developmental regression (present) , Myopathy (present) , Muscular dystrophy (present) , … (more)
Microcephaly (present) , Hypotonia (present) , Flexion contracture (present) , Respiratory insufficiency (present) , Developmental regression (present) , Myopathy (present) , Muscular dystrophy (present) , Cardiorespiratory arrest (present) , Developmental stagnation (present) (less)
Sex: male
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Likely pathogenic
(Dec 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503099.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Aug 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tibial muscular dystrophy
Myopathy, myofibrillar, 9, with early respiratory failure Dilated cardiomyopathy 1G Autosomal recessive limb-girdle muscular dystrophy type 2J Early-onset myopathy with fatal cardiomyopathy Hypertrophic cardiomyopathy 9
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002791108.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV004014222.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
Identified in a patient with Lambert-Eaton Myasthenic Syndrome (LEMS) who also harbored a pathogenic variant in the CACNA1S gene (Cerino et al., 2022); Not observed … (more)
Identified in a patient with Lambert-Eaton Myasthenic Syndrome (LEMS) who also harbored a pathogenic variant in the CACNA1S gene (Cerino et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies indicates this variant results in an insoluble protein due to improper folding (Hedburg et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22526018, 25500009, 23486992, 23446887, 34839411, 24636144, 35741838, 32039858, 34670883) (less)
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Likely pathogenic
(Jun 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004066464.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The p.P22667L variant (also known as c.68000C>T), located in coding exon 170 of the TTN gene, results from a C to T substitution at nucleotide … (more)
The p.P22667L variant (also known as c.68000C>T), located in coding exon 170 of the TTN gene, results from a C to T substitution at nucleotide position 68000. The proline at codon 22667 is replaced by leucine, an amino acid with similar properties. This variant (also referred to as p.P31732L and p.P30091L) has been detected in the homozygous and heterozygous states, including a de novo occurrence, in individuals with skeletal muscle and/or respiratory issues consistent with hereditary myopathy with early respiratory failure (HMERF). Homozygous individuals tended to be more severely affected, and not all heterozygous individuals were affected, suggesting this variant exhibits variable expressivity and reduced penetrance (Vasli N et al. Acta Neuropathol., 2012 Aug;124:273-83; Yue D et al. Neuromuscul. Disord., 2015 Feb;25:172-6; Palmio J et al. J Neurol Neurosurg Psychiatry, 2014 Mar;85:345-53; Pfeffer G et al. J. Neurol. Neurosurg. Psychiatry, 2014 Mar;85:331-8; Cerino M et al. Muscle Nerve, 2017 Nov;56:993-997; Savarese M et al. J Neuromuscul Dis, 2020;7:153-166; Rees M et al. Acta Neuropathol, 2021 Mar;141:431-453; Cerino M et al. Genes (Basel), 2022 Jun;13). Functional studies suggest this variant may be destabilizing and impact protein folding (Hedberg C et al. Neuromuscul. Disord. 2014 May;24(5):373-9; Rees M et al. Acta Neuropathol, 2021 Mar;141:431-453). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is likely pathogenic for hereditary myopathy with early respiratory failure; however, the association of this alteration with cardiomyopathy is unknown. (less)
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Pathogenic
(Apr 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002022468.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1G
Autosomal recessive limb-girdle muscular dystrophy type 2J
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000543162.8
First in ClinVar: Mar 24, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31732 of the TTN protein (p.Pro31732Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31732 of the TTN protein (p.Pro31732Leu). This variant is present in population databases (rs753334568, gnomAD 0.003%). This missense change has been observed in individual(s) with hereditary myopathy with early respiratory failure (HMERF) (PMID: 22526018, 23486992, 23606733, 25500009). In at least one individual the variant was observed to be de novo. This variant is also known as c.90272C>T (p.Pro30091Leu) and c.68576C>T (p.Pro22859Leu). ClinVar contains an entry for this variant (Variation ID: 132137). 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. (less)
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Pathogenic
(Dec 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248005.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000854982.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jan 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Primary familial dilated cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004804343.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: TTN c.87491C>T (p.Pro29164Leu) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Four of four … (more)
Variant summary: TTN c.87491C>T (p.Pro29164Leu) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248136 control chromosomes (gnomAD). c.87491C>T has been reported in the literature in multiple individuals with characteristic features of hereditary myopathy with early respiratory failure (Palmio_2013, Yue_2014, Hedberg_2014, Cerino_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in impaired protein solubility (Hedberg_2014). The following publications have been ascertained in the context of this evaluation (PMID: 35741838, 24231549, 23606733, 25500009). ClinVar contains an entry for this variant (Variation ID: 132137). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: research
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Dilated cardiomyopathy 1G
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805328.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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not provided
(-)
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no classification provided
Method: literature only
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Myopathy, myofibrillar, 9, with early respiratory failure
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000153727.4
First in ClinVar: May 30, 2014 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population. | Cerino M | Genes | 2022 | PMID: 35741838 |
Hereditary Myopathy with Early Respiratory Failure. | Adam MP | - | 2022 | PMID: 24575448 |
Making sense of missense variants in TTN-related congenital myopathies. | Rees M | Acta neuropathologica | 2021 | PMID: 33449170 |
Improved Criteria for the Classification of Titin Variants in Inherited Skeletal Myopathies. | Savarese M | Journal of neuromuscular diseases | 2020 | PMID: 32039858 |
Genetic Characterization of a French Cohort of GNE-mutation negative inclusion body myopathy patients with exome sequencing. | Cerino M | Muscle & nerve | 2017 | PMID: 28256728 |
Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. | Roberts AM | Science translational medicine | 2015 | PMID: 25589632 |
New disease allele and de novo mutation indicate mutational vulnerability of titin exon 343 in hereditary myopathy with early respiratory failure. | Yue D | Neuromuscular disorders : NMD | 2015 | PMID: 25500009 |
Hereditary myopathy with early respiratory failure is associated with misfolding of the titin fibronectin III 119 subdomain. | Hedberg C | Neuromuscular disorders : NMD | 2014 | PMID: 24636144 |
Hereditary myopathy with early respiratory failure is caused by mutations in the titin FN3 119 domain. | Hedberg C | Brain : a journal of neurology | 2014 | PMID: 24231549 |
Hereditary myopathy with early respiratory failure: occurrence in various populations. | Palmio J | Journal of neurology, neurosurgery, and psychiatry | 2014 | PMID: 23606733 |
Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure. | Pfeffer G | Journal of neurology, neurosurgery, and psychiatry | 2014 | PMID: 23486992 |
Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. | Ceyhan-Birsoy O | Neurology | 2013 | PMID: 23975875 |
Next generation sequencing for molecular diagnosis of neuromuscular diseases. | Vasli N | Acta neuropathologica | 2012 | PMID: 22526018 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN | - | - | - | - |
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Text-mined citations for rs753334568 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.