VCV000047409.20 - ClinVar

NM_001267550.2(TTN):c.82220T>C (p.Ile27407Thr)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(9); Likely benign(1)

10 out of 10 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001267550.2(TTN):c.82220T>C (p.Ile27407Thr)

Variation ID: 47409 Accession: VCV000047409.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q31.2 2: 178563912 (GRCh38) [ NCBI UCSC ] 2: 179428639 (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 31, 2015	May 1, 2024	May 6, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001267550.2:c.82220T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001254479.2:p.Ile27407Thr	missense
NM_001256850.1:c.77297T>C	NP_001243779.1:p.Ile25766Thr	missense
NM_003319.4:c.55025T>C	NP_003310.4:p.Ile18342Thr	missense
NM_133378.4:c.74516T>C	NP_596869.4:p.Ile24839Thr	missense
NM_133432.3:c.55400T>C	NP_597676.3:p.Ile18467Thr	missense
NM_133437.4:c.55601T>C	NP_597681.4:p.Ile18534Thr	missense
NC_000002.12:g.178563912A>G
NC_000002.11:g.179428639A>G
NG_011618.3:g.271891T>C
NG_051363.1:g.46086A>G
LRG_391:g.271891T>C

... more HGVS ... less HGVS

Protein change

I27407T, I24839T, I18342T, I25766T, I18467T, I18534T

Other names

Canonical SPDI

NC_000002.12:178563911:A:G

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.

0.00020 (G)

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

The Genome Aggregation Database (gnomAD) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00005

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Exome Aggregation Consortium (ExAC) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00004

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA140918 dbSNP: rs376037252 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	13204	35323
TTN-AS1	-	-	-	GRCh38	-	20314

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	Jun 19, 2014	RCV000040679.6
Myopathy, myofibrillar, 9, with early respiratory failure	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000265407.5
Autosomal recessive limb-girdle muscular dystrophy type 2J	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000300600.5
Dilated cardiomyopathy 1G	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000304128.5
Tibial muscular dystrophy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 10, 2019	RCV000361272.7
Early-onset myopathy with fatal cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000391590.5
not provided	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	May 6, 2021	RCV000726237.9
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Nov 20, 2018	RCV002345317.2

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 (Apr 26, 2017) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000701312.2 First in ClinVar: Jan 31, 2015 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: 3 Zygosity: Single Heterozygote Sex: mixed
Likely benign (May 06, 2021) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001774403.1 First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021	Comment: This variant is associated with the following publications: (PMID: 29263846)
Uncertain significance (Jun 19, 2014) C Contributing to aggregate classification	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: SCV000064370.6 First in ClinVar: May 03, 2013 Last updated: Dec 15, 2018	Comment: The Ile24839Thr variant in TTN has been identified by our laboratory in 1 adult with DCM. It was also identified in 1/8190 European American chromosomes … (more) The Ile24839Thr variant in TTN has been identified by our laboratory in 1 adult with DCM. It was also identified in 1/8190 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs3760 37252). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Additional information i s needed to fully assess the clinical significance of the Ile24839Thr variant. (less) Number of individuals with the variant: 2
Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dilated cardiomyopathy 1G Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000421415.3 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)
Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Myopathy, myofibrillar, 9, with early respiratory failure Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000421414.3 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)
Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Early-onset myopathy with fatal cardiomyopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000421411.3 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)
Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Tibial muscular dystrophy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000421416.3 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)
Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2J Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000421412.3 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)
Uncertain significance (Oct 10, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tibial muscular dystrophy Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368346.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in … (more) This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1. (less)
Uncertain significance (Nov 20, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002651067.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 29263846 Comment: The p.I18342T variant (also known as c.55025T>C), located in coding exon 153 of the TTN gene, results from a T to C substitution at nucleotide … (more) The p.I18342T variant (also known as c.55025T>C), located in coding exon 153 of the TTN gene, results from a T to C substitution at nucleotide position 55025. The isoleucine at codon 18342 is replaced by threonine, an amino acid with similar properties. This alteration, noted as p.I27407T (c.82220T>C) was reported in a subject with features of Bannayan-Riley-Ruvalcaba syndrome who was negative for PTEN alterations (Yehia L et al. NPJ Genom Med, 2017 Dec;2:37). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The Ile24839Thr variant in TTN has been identified by our laboratory in 1 adult with DCM. It was also identified in 1/8190 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs3760 37252). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Additional information i s needed to fully assess the clinical significance of the Ile24839Thr variant.

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 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.

Comment:

The p.I18342T variant (also known as c.55025T>C), located in coding exon 153 of the TTN gene, results from a T to C substitution at nucleotide position 55025. The isoleucine at codon 18342 is replaced by threonine, an amino acid with similar properties. This alteration, noted as p.I27407T (c.82220T>C) was reported in a subject with features of Bannayan-Riley-Ruvalcaba syndrome who was negative for PTEN alterations (Yehia L et al. NPJ Genom Med, 2017 Dec;2:37). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Germline TTN variants are enriched in PTEN-wildtype Bannayan-Riley-Ruvalcaba syndrome.	Yehia L	NPJ genomic medicine	2017	PMID: 29263846
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN	-	-	-	-

Text-mined citations for rs376037252 ...

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 Jan 19, 2025

ClinVar Genomic variation as it relates to human health

NM_001267550.2(TTN):c.82220T>C (p.Ile27407Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs376037252 ...