This variant is associated with the following publications: (PMID: 23476865)
ClinVar Genomic variation as it relates to human health
NM_133379.5(TTN):c.13364A>G (p.Lys4455Arg)
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.
(10)
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(4); Likely benign(2)
Uncertain significance(4); Likely benign(2)
10
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_133379.5(TTN):c.13364A>G (p.Lys4455Arg)
Variation ID: 47753 Accession: VCV000047753.49
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q31.2 2: 178749036 (GRCh38) [ NCBI UCSC ] 2: 179613763 (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 Dec 22, 2024 Apr 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001267550.2:c.11311+4088A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001256850.1:c.10360+4088A>G intron variant NM_003319.4:c.10222+4088A>G intron variant NM_133378.4:c.10360+4088A>G intron variant NM_133379.5:c.13364A>G NP_596870.2:p.Lys4455Arg missense NM_133432.3:c.10597+4088A>G intron variant NM_133437.4:c.10798+4088A>G intron variant NC_000002.12:g.178749036T>C NC_000002.11:g.179613763T>C NG_011618.3:g.86767A>G LRG_391:g.86767A>G LRG_391t2:c.13364A>G - Protein change
- K4455R
- Other names
-
p.K4455R:AAG>AGG
- Canonical SPDI
- NC_000002.12:178749035:T:C
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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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0.00080 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00029
Trans-Omics for Precision Medicine (TOPMed) 0.00038
Exome Aggregation Consortium (ExAC) 0.00041
The Genome Aggregation Database (gnomAD), exomes 0.00041
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00080
- 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 |
12178 | 32795 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 27, 2013 | RCV000041022.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 29, 2015 | RCV000415195.3 | |
| Conflicting classifications of pathogenicity (7) |
criteria provided, conflicting classifications
|
Apr 1, 2024 | RCV000726846.39 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 1, 2016 | RCV001198289.3 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(May 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000703597.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Likely benign
(Mar 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000238116.8
First in ClinVar: Jan 31, 2015 Last updated: Apr 09, 2018 |
Comment:
This variant is associated with the following publications: (PMID: 23476865)
|
|
|
Likely benign
(Apr 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001153134.28
First in ClinVar: Feb 03, 2020 Last updated: Dec 22, 2024 |
Comment:
TTN: BP4
Number of individuals with the variant: 3
|
|
|
Uncertain significance
(Oct 29, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Syncope
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492708.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
|
|
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Uncertain significance
(Aug 27, 2013)
|
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: SCV000064713.6
First in ClinVar: May 03, 2013 Last updated: Dec 15, 2018 |
Comment:
The Lys4455Arg variant in TTN has been identified by our laboratory in 1 Caucasi an individual with LVNC and bidirectional VT and has been identified … (more)
The Lys4455Arg variant in TTN has been identified by our laboratory in 1 Caucasi an individual with LVNC and bidirectional VT and has been identified in 1/8588 E uropean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS/; dbSNP rs142304137). Computational analyses are limited or unavailable for this variant. Additional information is needed to fully assess its clinical significance. (less)
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Tibial muscular dystrophy
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369170.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Uncertain significance.
|
|
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Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552805.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TTN p.Lys4455Arg variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was … (more)
The TTN p.Lys4455Arg variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs142304137), ClinVar (conflicting interpretations of pathogenicity, associated with syncope and hypertrophic cardiomyopathy; classified as Uncertain Significance by Laboratory for Molecular Medicine at Partners Healthcare, Centre for Mendelian Genomics at University Medical Centre Ljubljana, EGL Genetic Diagnostics and classified as Likely Benign by GeneDx), and LOVD 3.0. The variant was not identified in the Cosmic database. The variant was identified in control databases in 110 of 280462 chromosomes at a frequency of 0.000392 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 30 of 30546 chromosomes (freq: 0.000982), European (non-Finnish) in 62 of 128212 chromosomes (freq: 0.000484), Other in 3 of 7108 chromosomes (freq: 0.000422), Latino in 13 of 35210 chromosomes (freq: 0.000369), African in 2 of 24318 chromosomes (freq: 0.000082), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The variant was identified in a 5 year old asymptomatic female who presented with sinus bradycardia and was found to have exercise-induced bidirectional VT and a hypertrabeculated left ventricle (Egan_2013_PMID: 23476865). A pan cardiomyopathy microarray identified three missense variants in this individual: RYR2 p.Arg169Gln, CASQ2 p.Asp398del, and TTN p.Lys4455Arg (Egan_2013_PMID: 23476865). Four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing, specificically a decrease in 5’ splicing activity at the variant location. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
|
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743009.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798696.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955850.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
Comment:
Comment:
TTN: BP4
Comment:
The Lys4455Arg variant in TTN has been identified by our laboratory in 1 Caucasi an individual with LVNC and bidirectional VT and has been identified in 1/8588 E uropean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS/; dbSNP rs142304137). Computational analyses are limited or unavailable for this variant. Additional information is needed to fully assess its clinical significance.
Comment:
This variant was classified as: Uncertain significance.
Comment:
The TTN p.Lys4455Arg variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs142304137), ClinVar (conflicting interpretations of pathogenicity, associated with syncope and hypertrophic cardiomyopathy; classified as Uncertain Significance by Laboratory for Molecular Medicine at Partners Healthcare, Centre for Mendelian Genomics at University Medical Centre Ljubljana, EGL Genetic Diagnostics and classified as Likely Benign by GeneDx), and LOVD 3.0. The variant was not identified in the Cosmic database. The variant was identified in control databases in 110 of 280462 chromosomes at a frequency of 0.000392 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 30 of 30546 chromosomes (freq: 0.000982), European (non-Finnish) in 62 of 128212 chromosomes (freq: 0.000484), Other in 3 of 7108 chromosomes (freq: 0.000422), Latino in 13 of 35210 chromosomes (freq: 0.000369), African in 2 of 24318 chromosomes (freq: 0.000082), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The variant was identified in a 5 year old asymptomatic female who presented with sinus bradycardia and was found to have exercise-induced bidirectional VT and a hypertrabeculated left ventricle (Egan_2013_PMID: 23476865). A pan cardiomyopathy microarray identified three missense variants in this individual: RYR2 p.Arg169Gln, CASQ2 p.Asp398del, and TTN p.Lys4455Arg (Egan_2013_PMID: 23476865). Four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing, specificically a decrease in 5’ splicing activity at the variant location. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
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:
This variant is associated with the following publications: (PMID: 23476865)
Comment:
TTN: BP4
Comment:
The Lys4455Arg variant in TTN has been identified by our laboratory in 1 Caucasi an individual with LVNC and bidirectional VT and has been identified in 1/8588 E uropean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS/; dbSNP rs142304137). Computational analyses are limited or unavailable for this variant. Additional information is needed to fully assess its clinical significance.
Comment:
This variant was classified as: Uncertain significance.
Comment:
The TTN p.Lys4455Arg variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs142304137), ClinVar (conflicting interpretations of pathogenicity, associated with syncope and hypertrophic cardiomyopathy; classified as Uncertain Significance by Laboratory for Molecular Medicine at Partners Healthcare, Centre for Mendelian Genomics at University Medical Centre Ljubljana, EGL Genetic Diagnostics and classified as Likely Benign by GeneDx), and LOVD 3.0. The variant was not identified in the Cosmic database. The variant was identified in control databases in 110 of 280462 chromosomes at a frequency of 0.000392 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 30 of 30546 chromosomes (freq: 0.000982), European (non-Finnish) in 62 of 128212 chromosomes (freq: 0.000484), Other in 3 of 7108 chromosomes (freq: 0.000422), Latino in 13 of 35210 chromosomes (freq: 0.000369), African in 2 of 24318 chromosomes (freq: 0.000082), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The variant was identified in a 5 year old asymptomatic female who presented with sinus bradycardia and was found to have exercise-induced bidirectional VT and a hypertrabeculated left ventricle (Egan_2013_PMID: 23476865). A pan cardiomyopathy microarray identified three missense variants in this individual: RYR2 p.Arg169Gln, CASQ2 p.Asp398del, and TTN p.Lys4455Arg (Egan_2013_PMID: 23476865). Four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing, specificically a decrease in 5’ splicing activity at the variant location. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN | - | - | - | - |
Text-mined citations for rs142304137 ...
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 Jan 19, 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.