The p.Arg7250Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.15% (15/9798) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs201418615). Computational prediction tools and conservation analysis d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Arg7250Gln variant is uncertain.
ClinVar Genomic variation as it relates to human health
NM_001267550.2(TTN):c.25481G>A (p.Arg8494Gln)
Germline
Classification
Help
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.
(9)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(2); Likely benign(5)
Uncertain significance(2); Likely benign(5)
9
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001267550.2(TTN):c.25481G>A (p.Arg8494Gln)
Variation ID: 192175 Accession: VCV000192175.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q31.2 2: 178717253 (GRCh38) [ NCBI UCSC ] 2: 179581980 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 28, 2024 Jan 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001267550.2:c.25481G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001254479.2:p.Arg8494Gln missense NM_001256850.1:c.24530G>A NP_001243779.1:p.Arg8177Gln missense NM_003319.4:c.13282+20829G>A intron variant NM_133378.4:c.21749G>A NP_596869.4:p.Arg7250Gln missense NM_133432.3:c.13657+20829G>A intron variant NM_133437.4:c.13858+20829G>A intron variant NC_000002.12:g.178717253C>T NC_000002.11:g.179581980C>T NG_011618.3:g.118550G>A LRG_391:g.118550G>A - Protein change
- R7250Q, R8494Q, R8177Q
- Other names
- -
- Canonical SPDI
- NC_000002.12:178717252:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.00080 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00013
The Genome Aggregation Database (gnomAD), exomes 0.00014
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00033
Trans-Omics for Precision Medicine (TOPMed) 0.00057
The Genome Aggregation Database (gnomAD) 0.00058
1000 Genomes Project 0.00080
1000 Genomes Project 30x 0.00094
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| TTN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
11838 | 31483 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Aug 17, 2023 | RCV000172687.18 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Aug 24, 2020 | RCV000215717.11 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV001083467.8 |
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. |
|
|---|---|---|---|---|---|
|
Likely benign
(Jun 24, 2013)
|
criteria provided, single submitter
Method: research
|
Not provided
Affected status: unknown
Allele origin:
unknown
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000055047.1 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
|
Number of individuals with the variant: 2
|
|
|
Uncertain significance
(Aug 29, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232857.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Uncertain significance
(Jul 29, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000272603.3
First in ClinVar: May 29, 2016 Last updated: Dec 15, 2018 |
Comment:
The p.Arg7250Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.15% (15/9798) of African chrom osomes … (more)
The p.Arg7250Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.15% (15/9798) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs201418615). Computational prediction tools and conservation analysis d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Arg7250Gln variant is uncertain. (less)
Number of individuals with the variant: 1
|
|
|
Likely benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000555448.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
|
|
|
Likely benign
(Aug 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001431968.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Comment:
Variant summary: TTN c.21749G>A (p.Arg7250Gln) results in a conservative amino acid change located in the I-band domain of the encoded protein sequence. Four of five … (more)
Variant summary: TTN c.21749G>A (p.Arg7250Gln) results in a conservative amino acid change located in the I-band domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 280342 control chromosomes, predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.21749G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with another pathogenic variant has been internally reported (TTR c.424G>A, p.V142I), providing supporting evidence for a benign role. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Likely benign
(Oct 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000714643.2
First in ClinVar: Apr 09, 2018 Last updated: Sep 25, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 27604489, 23861362)
|
|
|
Likely benign
(Aug 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003824797.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919643.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966755.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
Comment:
Comment:
Variant summary: TTN c.21749G>A (p.Arg7250Gln) results in a conservative amino acid change located in the I-band domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 280342 control chromosomes, predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.21749G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with another pathogenic variant has been internally reported (TTR c.424G>A, p.V142I), providing supporting evidence for a benign role. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This variant is associated with the following publications: (PMID: 27604489, 23861362)
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. |
Comment:
The p.Arg7250Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.15% (15/9798) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs201418615). Computational prediction tools and conservation analysis d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Arg7250Gln variant is uncertain.
Comment:
Variant summary: TTN c.21749G>A (p.Arg7250Gln) results in a conservative amino acid change located in the I-band domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 280342 control chromosomes, predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.21749G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with another pathogenic variant has been internally reported (TTR c.424G>A, p.V142I), providing supporting evidence for a benign role. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This variant is associated with the following publications: (PMID: 27604489, 23861362)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN | - | - | - | - |
Text-mined citations for rs201418615 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.