ClinVar Genomic variation as it relates to human health
NM_001267550.2(TTN):c.60932G>A (p.Arg20311Gln)
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.
Uncertain significance(11); Benign(2); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001267550.2(TTN):c.60932G>A (p.Arg20311Gln)
Variation ID: 191930 Accession: VCV000191930.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q31.2 2: 178590793 (GRCh38) [ NCBI UCSC ] 2: 179455520 (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 Jun 8, 2015 Nov 24, 2024 Nov 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001267550.2:c.60932G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001254479.2:p.Arg20311Gln missense NM_001256850.1:c.56009G>A NP_001243779.1:p.Arg18670Gln missense NM_001267550.1:c.60932G>A NM_003319.4:c.33737G>A NP_003310.4:p.Arg11246Gln missense NM_133378.4:c.53228G>A NP_596869.4:p.Arg17743Gln missense NM_133432.3:c.34112G>A NP_597676.3:p.Arg11371Gln missense NM_133437.4:c.34313G>A NP_597681.4:p.Arg11438Gln missense NC_000002.12:g.178590793C>T NC_000002.11:g.179455520C>T NG_011618.3:g.245010G>A NG_051363.1:g.72967C>T LRG_391:g.245010G>A - Protein change
- R17743Q, R20311Q, R11246Q, R11371Q, R11438Q, R18670Q
- Other names
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- Canonical SPDI
- NC_000002.12:178590792:C: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00005
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00008
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- Links
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 |
12044 | 32096 | |
TTN-AS1 | - | - | - | GRCh38 | - | 18402 |
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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Benign (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000283208.5 | |
Benign (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000400629.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000401451.5 | |
Likely benign (1) |
criteria provided, single submitter
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Dec 15, 2019 | RCV002453600.2 | |
TTN-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Sep 28, 2022 | RCV004535172.1 |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 22, 2023 | RCV000172296.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 10, 2023 | RCV000220034.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 28, 2019 | RCV000297539.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000341926.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 20, 2017 | RCV000558110.4 |
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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Uncertain significance
(Jun 24, 2013)
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criteria provided, single submitter
Method: research
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Not provided
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000054969.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
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Number of individuals with the variant: 1
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Uncertain significance
(Apr 20, 2017)
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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
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000643465.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Uncertain significance
(Jan 11, 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: SCV000705226.2
First in ClinVar: May 29, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
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Uncertain significance
(Jun 25, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000272713.3
First in ClinVar: May 29, 2016 Last updated: Dec 15, 2018 |
Comment:
The p.Arg17743Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 7/8474 East Asian chromosomes b y … (more)
The p.Arg17743Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 7/8474 East Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373062007). Computational prediction tools and conservation analysis suggest t hat this variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, the clinical significance of t he p.Arg17743Gln variant is uncertain. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Sep 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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TTN-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004114076.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TTN c.60932G>A variant is predicted to result in the amino acid substitution p.Arg20311Gln. To our knowledge, this variant has not been reported in the … (more)
The TTN c.60932G>A variant is predicted to result in the amino acid substitution p.Arg20311Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.093% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179455520-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(May 22, 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: SCV004237054.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely benign
(Dec 15, 2019)
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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: SCV002614411.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Aug 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1G
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005398451.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
A heterozygous missense variant was identified, NM_001267550.1(TTN):c.60932G>A in exon 304 of 363 of the TTN gene. This substitution is predicted to create a minor amino … (more)
A heterozygous missense variant was identified, NM_001267550.1(TTN):c.60932G>A in exon 304 of 363 of the TTN gene. This substitution is predicted to create a minor amino acid change from arginine to glutamine at position 20311 of the protein, NP_001254479.1(TTN):p.(Arg20311Gln). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the A-band region. In silico software predicts this variant to be pathogenic (Polyphen, CADD, Mutation Taster). The variant is present in the gnomAD population database at frequencies of 0.09% (18 heterozygotes, 0 homozygotes) and 0.009% (25 heterozygotes, 0 homozygotes) in the East Asian subpopulation and the global population, respectively. It has been previously reported as a VUS in clinical cases (ClinVar, LOVD). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). (less)
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Benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Tibial muscular dystrophy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000422513.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
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 … (more)
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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2J
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000422510.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1G
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000422514.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
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 … (more)
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. (less)
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Benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Myopathy, myofibrillar, 9, with early respiratory failure
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000422511.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
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 … (more)
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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Early-onset myopathy with fatal cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000422512.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Nov 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223684.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: TTN c.53228G>A (p.Arg17743Gln) results in a conservative amino acid change located in the A-band domain of the encoded protein sequence. Two of four … (more)
Variant summary: TTN c.53228G>A (p.Arg17743Gln) results in a conservative amino acid change located in the A-band domain of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 247214 control chromosomes (gnomAD). To our knowledge, no occurrence of c.53228G>A in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=4), likely benign (n=1) and benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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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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http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN | - | - | - | - |
Text-mined citations for rs373062007 ...
HelpRecord last updated Nov 30, 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.