This variant is associated with the following publications: (PMID: 27930701, 28255936, 17344846)
ClinVar Genomic variation as it relates to human health
NM_001267550.2(TTN):c.81899G>A (p.Arg27300His)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Uncertain significance(5); Benign(1); Likely benign(6)
Uncertain significance(5); Benign(1); Likely benign(6)
12 out of 12 submissions contributed to this 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.
12
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001267550.2(TTN):c.81899G>A (p.Arg27300His)
Variation ID: 47404 Accession: VCV000047404.65
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q31.2 2: 178564233 (GRCh38) [ NCBI UCSC ] 2: 179428960 (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 Jan 13, 2017 Oct 25, 2025 Apr 9, 2025 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001267550.2:c.81899G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001254479.2:p.Arg27300His missense NM_001256850.1:c.76976G>A NP_001243779.1:p.Arg25659His missense NM_001267550.1:c.81899G>A NM_003319.4:c.54704G>A NP_003310.4:p.Arg18235His missense NM_133378.4:c.74195G>A NP_596869.4:p.Arg24732His missense NM_133432.3:c.55079G>A NP_597676.3:p.Arg18360His missense NM_133437.4:c.55280G>A NP_597681.4:p.Arg18427His missense NC_000002.12:g.178564233C>T NC_000002.11:g.179428960C>T NG_011618.3:g.271570G>A NG_051363.1:g.46407C>T LRG_391:g.271570G>A Q8WZ42:p.Arg25659His - Protein change
- R27300H, R24732H, R25659H, R18235H, R18360H, R18427H
- Other names
-
p.R25659H:CGT>CAT
- Canonical SPDI
- NC_000002.12:178564232:C:T
-
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.
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The Genome Aggregation Database (gnomAD) 0.00036
The Genome Aggregation Database (gnomAD) 0.00040
The Genome Aggregation Database (gnomAD), exomes 0.00037
Trans-Omics for Precision Medicine (TOPMed) 0.00050
Exome Aggregation Consortium (ExAC) 0.00031
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00058
- 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 | ||
|---|---|---|---|---|---|---|
| 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 |
13849 | 37088 | |
| TTN-AS1 | - | - | - | GRCh38 | - | 21352 |
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 classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Apr 9, 2025 | RCV000040674.16 | |
| Conflicting classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Apr 1, 2025 | RCV000176835.49 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 17, 2017 | RCV000227596.8 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 12, 2014 | RCV000415094.3 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jun 8, 2020 | RCV000619262.5 | |
| Benign (1) |
criteria provided, single submitter
|
Jun 16, 2023 | RCV000768910.5 |
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. |
Expand all rows
Collapse all rows
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
(Jan 11, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Athena Diagnostics
Accession: SCV001879709.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Likely benign
(Oct 23, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000237620.3
First in ClinVar: Jul 05, 2015 Last updated: Apr 09, 2018 |
Comment:
show
This variant is associated with the following publications: (PMID: 27930701, 28255936, 17344846) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(Sep 11, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766501.2
First in ClinVar: Dec 24, 2022 Last updated: Nov 04, 2023 |
Comment:
show
Variant summary: TTN c.74195G>A (p.Arg24732His) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 247888 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Cardiomyopathy (0.00037 vs 0.00063), allowing no conclusion about variant significance. c.74195G>A has been reported in the literature in individuals who suffered a sudden unexplained cardiac death (e.g. Campuzano_2015, Campuzano_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 28255936). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS or likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Jun 07, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000333425.4
First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 4
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Likely benign
(Apr 09, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV006066802.1
First in ClinVar: May 03, 2025 Last updated: May 03, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
|
|
|
Uncertain significance
(Dec 12, 2014)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Myopathy |
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492653.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Uncertain significance
(Oct 17, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Dilated cardiomyopathy 1G
Autosomal recessive limb-girdle muscular dystrophy type 2J |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000286856.4
First in ClinVar: Jul 01, 2016 Last updated: May 26, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Mar 06, 2013)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000064365.6
First in ClinVar: May 03, 2013 Last updated: Dec 15, 2018 |
Comment:
show
Arg24732His in exon 275 of TTN: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, multiple mammals (guinea pig, hedgehog, elephant, rock hyrax, and platypus) have a histidine (His) at this position, despite high nearby amino acid conserv ation. In addition, computational analyses (biochemical properties, AlignGVGD, a nd PolyPhen2) do not suggest a high likelihood of impact to the protein. This va riant has been identified in 5/8226 European American chromosomes from a broad p opulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs55850344). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Oct 21, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714637.2
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 5
|
|
|
Benign
(Jun 16, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiomyopathy |
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900283.3 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Jun 08, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Ambry Genetics
Accession: SCV000735249.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Apr 01, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000608994.39
First in ClinVar: Oct 30, 2017 Last updated: Oct 25, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 5
|
|
Comment:
Comment:
Variant summary: TTN c.74195G>A (p.Arg24732His) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 247888 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Cardiomyopathy (0.00037 vs 0.00063), allowing no conclusion about variant significance. c.74195G>A has been reported in the literature in individuals who suffered a sudden unexplained cardiac death (e.g. Campuzano_2015, Campuzano_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 28255936). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS or likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
Arg24732His in exon 275 of TTN: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, multiple mammals (guinea pig, hedgehog, elephant, rock hyrax, and platypus) have a histidine (His) at this position, despite high nearby amino acid conserv ation. In addition, computational analyses (biochemical properties, AlignGVGD, a nd PolyPhen2) do not suggest a high likelihood of impact to the protein. This va riant has been identified in 5/8226 European American chromosomes from a broad p opulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs55850344).
Comment:
BP4
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 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.
Comment:
TTN: BP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy. | Mademont-Soler I | PloS one | 2017 | PMID: 28771489 |
| Sudden Arrhythmic Death During Exercise: A Post-Mortem Genetic Analysis. | Campuzano O | Sports medicine (Auckland, N.Z.) | 2017 | PMID: 28255936 |
| Correction: Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation. | Sanchez O | PloS one | 2017 | PMID: 28166282 |
| Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation. | Sanchez O | PloS one | 2016 | PMID: 27930701 |
| Rare Titin (TTN) Variants in Diseases Associated with Sudden Cardiac Death. | Campuzano O | International journal of molecular sciences | 2015 | PMID: 26516846 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN | - | - | - | - |
Text-mined citations for rs55850344 ...
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 Oct 26, 2025
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.