ClinVar Genomic variation as it relates to human health
NM_001267550.2(TTN):c.107840T>A (p.Ile35947Asn)
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.107840T>A (p.Ile35947Asn)
Variation ID: 12654 Accession: VCV000012654.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q31.2 2: 178527148 (GRCh38) [ NCBI UCSC ] 2: 179391875 (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 Apr 4, 2013 Feb 28, 2024 Mar 30, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001267550.2:c.107840T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001254479.2:p.Ile35947Asn missense NM_001256850.1:c.102917T>A NP_001243779.1:p.Ile34306Asn missense NM_003319.4:c.80645T>A NP_003310.4:p.Ile26882Asn missense NM_133378.4:c.100136T>A NP_596869.4:p.Ile33379Asn missense NM_133432.3:c.81020T>A NP_597676.3:p.Ile27007Asn missense NM_133437.4:c.81221T>A NP_597681.4:p.Ile27074Asn missense NC_000002.12:g.178527148A>T NC_000002.11:g.179391875A>T NG_011618.3:g.308655T>A NG_051363.1:g.9322A>T LRG_391:g.308655T>A LRG_391t1:c.107840T>A LRG_391p1:p.Ile35947Asn - Protein change
- I33379N, I34306N, I35947N, I27007N, I27074N, I26882N
- Other names
- 293329T-A
- AJ277892.2:g.293329T>A
- Canonical SPDI
- NC_000002.12:178527147:A:T
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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.
Exome Aggregation Consortium (ExAC) 0.00001
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 |
11689 | 31012 | |
TTN-AS1 | - | - | - | GRCh38 | - | 17732 |
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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Pathogenic (3) |
criteria provided, single submitter
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Feb 12, 2020 | RCV000013490.26 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2022 | RCV001319595.4 |
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
(Mar 30, 2022)
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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: SCV001510348.4
First in ClinVar: Mar 14, 2021 Last updated: Feb 28, 2024 |
Comment:
Experimental studies have shown that this missense change does not substantially affect TTN function (25877298 25739468). Algorithms developed to predict the effect of variants on … (more)
Experimental studies have shown that this missense change does not substantially affect TTN function (25877298 25739468). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 12654). This variant is also known as ATT>AAT change at position 293,329, I35947N, or I57N. This missense change has been observed in individual(s) with clinical features of autosomal recessive TTN-related conditions (PMID: 27796757; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant tibial muscular dystrophy (PMID: 12891679); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs281864928, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 35947 of the TTN protein (p.Ile35947Asn). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is located in the M band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). (less)
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Pathogenic
(Feb 12, 2020)
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criteria provided, single submitter
Method: clinical testing
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Tibial muscular dystrophy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149973.2
First in ClinVar: Feb 03, 2020 Last updated: Aug 20, 2020 |
Observation 1:
Clinical Features:
Dysphagia (present) , Muscular dystrophy (present) , Distal muscle weakness (present) , Increased intramuscular fat (present)
Sex: female
Tissue: blood
Observation 2:
Clinical Features:
Myopathy (present)
Sex: male
Tissue: blood
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Pathogenic
(Aug 01, 2003)
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no assertion criteria provided
Method: literature only
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TIBIAL MUSCULAR DYSTROPHY, TARDIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033737.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In affected members of a Belgian family with tibial muscular dystrophy (TMD; 600334), Van den Bergh et al. (2003) identified a heterozygous 293329T-A change in … (more)
In affected members of a Belgian family with tibial muscular dystrophy (TMD; 600334), Van den Bergh et al. (2003) identified a heterozygous 293329T-A change in the Mex6 exon of the TTN gene, resulting in an ile-to-asn substitution. The family showed incomplete disease penetrance. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Tibial muscular dystrophy
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000054697.4
First in ClinVar: Apr 04, 2013 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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Udd Distal Myopathy – Tibial Muscular Dystrophy. | Adam MP | - | 2020 | PMID: 20301498 |
Targeted Next-Generation Sequencing Reveals Novel TTN Mutations Causing Recessive Distal Titinopathy. | Evilä A | Molecular neurobiology | 2017 | PMID: 27796757 |
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 |
Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. | Ceyhan-Birsoy O | Neurology | 2013 | PMID: 23975875 |
Tibial muscular dystrophy in a Belgian family. | Van den Bergh PY | Annals of neurology | 2003 | PMID: 12891679 |
Text-mined citations for rs281864928 ...
HelpRecord last updated Apr 20, 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.