VCV000178242.51 - ClinVar

NM_001267550.2(TTN):c.21548G>A (p.Cys7183Tyr)

Germline

Classification

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.

(16)

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(7); Benign(1); Likely benign(5)

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.21548G>A (p.Cys7183Tyr)

Variation ID: 178242 Accession: VCV000178242.51

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q31.2 2: 178723552 (GRCh38) [ NCBI UCSC ] 2: 179588279 (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	Oct 20, 2024	Oct 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001267550.2:c.21548G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001254479.2:p.Cys7183Tyr	missense
NM_001256850.1:c.20597G>A	NP_001243779.1:p.Cys6866Tyr	missense
NM_003319.4:c.13282+14530G>A		intron variant
NM_133378.4:c.17816G>A	NP_596869.4:p.Cys5939Tyr	missense
NM_133432.3:c.13657+14530G>A		intron variant
NM_133437.4:c.13858+14530G>A		intron variant
NC_000002.12:g.178723552C>T
NC_000002.11:g.179588279C>T
NG_011618.3:g.112251G>A
LRG_391:g.112251G>A
LRG_391t1:c.21548G>A

... more HGVS ... less HGVS

Protein change

C5939Y, C7183Y, C6866Y

Other names

p.C6866Y:TGC>TAC

Canonical SPDI

NC_000002.12:178723551:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00100 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00035

The Genome Aggregation Database (gnomAD), exomes 0.00041

The Genome Aggregation Database (gnomAD) 0.00042

Trans-Omics for Precision Medicine (TOPMed) 0.00055

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00084

1000 Genomes Project 0.00100

1000 Genomes Project 30x 0.00109

Links

ClinGen: CA181891 dbSNP: rs189951108 VarSome

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
Gene	OMIM	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	11970	31891

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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Sep 12, 2017	RCV000154980.19
not provided	Conflicting interpretations of pathogenicity (11)	criteria provided, conflicting classifications	Oct 5, 2023	RCV000172692.50
Autosomal recessive limb-girdle muscular dystrophy type 2J Dilated cardiomyopathy 1G	Uncertain significance (1)	criteria provided, single submitter	Nov 17, 2017	RCV000473052.14
Arrhythmogenic right ventricular cardiomyopathy	Likely benign (1)	criteria provided, single submitter	Apr 9, 2019	RCV000852895.9
Cardiomyopathy	Benign (1)	criteria provided, single submitter	May 16, 2023	RCV001170082.12
TTN-related disorder	Uncertain significance (1)	criteria provided, single submitter	Apr 25, 2023	RCV004534978.1

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 (Nov 17, 2017)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Dilated cardiomyopathy 1G Autosomal recessive limb-girdle muscular dystrophy type 2J Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000542602.3 First in ClinVar: Apr 17, 2017 Last updated: May 26, 2018
Uncertain significance (Sep 12, 2017)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000204662.5 First in ClinVar: Jan 31, 2015 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 23861362 Comment: The p.Cys5939Tyr variant in TTN has been identified by our laboratory in 1 indiv idual with RCM and 1 with HCM; however, both individuals harbor … (more) The p.Cys5939Tyr variant in TTN has been identified by our laboratory in 1 indiv idual with RCM and 1 with HCM; however, both individuals harbor pathogenic varia nts in other genes responsible for their symptoms. This variant has been identif ied in 76/126152 of European chromosomes by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org/; dbSNP rs189951108) and has been reported in ClinVar (Variation ID: 178242). Computational prediction tools and conservat ion analysis suggest that the p.Cys5939Tyr variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, the clinical significance of the p.Cys5939Tyr variant is uncertain. (less) Number of individuals with the variant: 4
Likely benign (Jan 10, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000844640.2 First in ClinVar: Aug 19, 2017 Last updated: Jan 18, 2020
Likely benign (Oct 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003818548.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Benign (May 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001332621.3 First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024
Likely benign (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	Not provided Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000051259.1 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: 1
Uncertain significance (Jan 19, 2018)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000336057.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN Number of individuals with the variant: 6 Sex: mixed
Likely benign (Apr 09, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular cardiomyopathy Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995631.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
Uncertain significance (Jan 04, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001159319.2 First in ClinVar: Feb 10, 2020 Last updated: Jan 08, 2022	Comment: The TTN c.21548G>A; p.Cys7183Tyr variant (rs189951108; ClinVar Variation ID: 178242) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and … (more) The TTN c.21548G>A; p.Cys7183Tyr variant (rs189951108; ClinVar Variation ID: 178242) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Cys7183Tyr variant cannot be determined with certainty. Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. (less)
Likely benign (Nov 06, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000238297.6 First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 23861362, 28771489)
Uncertain significance (Apr 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	TTN-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120456.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The TTN c.21548G>A variant is predicted to result in the amino acid substitution p.Cys7183Tyr. To our knowledge, this variant has not been reported in the … (more) The TTN c.21548G>A variant is predicted to result in the amino acid substitution p.Cys7183Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179588279-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (May 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713248.2 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Publications: PubMed (1) PubMed: 28697927 Number of individuals with the variant: 5
Uncertain significance (Dec 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000493407.23 First in ClinVar: Jul 05, 2015 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (-)	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: SCV001740066.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Uncertain significance (-)	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: SCV001921796.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (-)	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: SCV001973819.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

The p.Cys5939Tyr variant in TTN has been identified by our laboratory in 1 indiv idual with RCM and 1 with HCM; however, both individuals harbor pathogenic varia nts in other genes responsible for their symptoms. This variant has been identif ied in 76/126152 of European chromosomes by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org/; dbSNP rs189951108) and has been reported in ClinVar (Variation ID: 178242). Computational prediction tools and conservat ion analysis suggest that the p.Cys5939Tyr variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, the clinical significance of the p.Cys5939Tyr variant is uncertain.

Comment:

The TTN c.21548G>A; p.Cys7183Tyr variant (rs189951108; ClinVar Variation ID: 178242) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Cys7183Tyr variant cannot be determined with certainty. Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068.

Comment:

The TTN c.21548G>A variant is predicted to result in the amino acid substitution p.Cys7183Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179588279-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A Unique Case of Type-1 Facioscapulohumeral Muscular Dystrophy and Sarcomeric Hypertrophic Cardiomyopathy.	Lima da Silva G	Revista espanola de cardiologia (English ed.)	2018	PMID: 28697927
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 rs189951108 ...

These 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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_001267550.2(TTN):c.21548G>A (p.Cys7183Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs189951108 ...